VCV000001324.59 - ClinVar

NM_030973.4(MED25):c.1004C>T (p.Ala335Val)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(15)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(1); Likely benign(5)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_030973.4(MED25):c.1004C>T (p.Ala335Val)

Variation ID: 1324 Accession: VCV000001324.59

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.33 19: 49830790 (GRCh38) [ NCBI UCSC ] 19: 50334047 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 1, 2013	Dec 22, 2024	Oct 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_030973.4:c.1004C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_112235.2:p.Ala335Val	missense
NM_001378355.1:c.1004C>T	NP_001365284.1:p.Ala335Val	missense
NC_000019.10:g.49830790C>T
NC_000019.9:g.50334047C>T
NG_017091.1:g.17512C>T
LRG_368:g.17512C>T
LRG_368t1:c.1004C>T	LRG_368p1:p.Ala335Val
	Q71SY5:p.Ala335Val

... more HGVS ... less HGVS

Protein change

Other names

A335V

Canonical SPDI

NC_000019.10:49830789:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00100 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00100

1000 Genomes Project 30x 0.00109

Exome Aggregation Consortium (ExAC) 0.00368

The Genome Aggregation Database (gnomAD), exomes 0.00384

Trans-Omics for Precision Medicine (TOPMed) 0.00413

The Genome Aggregation Database (gnomAD) 0.00443

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00500

Links

UniProtKB: Q71SY5#VAR_063521 OMIM: 610197.0001 dbSNP: rs145770066 ClinGen: CA248234 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MED25		-	-	GRCh38 GRCh37	719	750

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Charcot-Marie-Tooth disease type 2B2	Uncertain significance (2)	no assertion criteria provided	Oct 1, 2009	RCV000001387.18
Charcot-Marie-Tooth disease	Likely benign (1)	criteria provided, single submitter	-	RCV000192241.11
not provided	Conflicting classifications of pathogenicity (6)	criteria provided, conflicting classifications	Oct 1, 2024	RCV000416086.44
not specified	Uncertain significance (1)	criteria provided, single submitter	Nov 14, 2020	RCV001818117.11
Charcot-Marie-Tooth disease type 2	Likely benign (1)	criteria provided, single submitter	Jan 29, 2024	RCV001082848.16
Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome	Likely benign (2)	criteria provided, multiple submitters, no conflicts	Nov 6, 2023	RCV001262290.20
Tip-toe gait	Likely pathogenic (1)	no assertion criteria provided	-	RCV002227925.10
MED25-related disorder	Likely benign (1)	no assertion criteria provided	Jul 15, 2020	RCV003924791.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease Affected status: yes Allele origin: germline	Molecular Genetics Laboratory, London Health Sciences Centre Accession: SCV001335736.1 First in ClinVar: Jun 15, 2020 Last updated: Jun 15, 2020
Likely benign (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440104.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020
Uncertain significance (Nov 14, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002065977.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Benign (Aug 22, 2023)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Mendelics Accession: SCV001135137.2 First in ClinVar: Jan 09, 2020 Last updated: Aug 25, 2023
Uncertain significance (Aug 15, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000233169.5 First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MED25 Number of individuals with the variant: 6 Zygosity: Single Heterozygote Sex: mixed
Likely benign (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease type 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000259555.10 First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024
Likely benign (Nov 06, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001477651.5 First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024
Likely benign (Oct 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000493228.34 First in ClinVar: Jan 30, 2017 Last updated: Dec 22, 2024	Comment: MED25: BS2 Number of individuals with the variant: 34
Uncertain significance (Oct 01, 2009)	no assertion criteria provided Method: literature only	RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000021537.6 First in ClinVar: Apr 04, 2013 Last updated: May 09, 2020	Publications: PubMed (2) PubMed: 25488817‚ 30039206 Comment on evidence: This variant, formerly titled CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B2 based on the report of Leal et al. (2009), has been reclassified based on the report … (more) This variant, formerly titled CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B2 based on the report of Leal et al. (2009), has been reclassified based on the report of Leal et al. (2018). In affected members of a large, highly consanguineous Costa Rican family with Charcot-Marie-Tooth disease type 2B2 (CMT2B2; 605589), Leal et al. (2009) identified a homozygous 1004C-T transition in the MED25 gene, resulting in an ala335-to-val (A335V) substitution. The family was from a single town in the province of Alajuela. Carrier frequency of the A335V variant in this population was estimated to be 0.68% (allele frequency of 0.34%). The A335V variant affects a highly conserved residue in a region predicted to be an interaction site for the SH3 domain of the Abelson tyrosine kinase family (see ABL1; 189980). Studies of synthetic MED25 peptides showed that the A335V variant had similar binding affinity as wildtype for the SH3 domain of ABL. However, it also showed high affinity for the SH3 domain of the Src family kinase LCK (153390), which wildtype MED25 did not. Thus, the A335V variant showed a loss of SH3 binding specificity. Leal et al. (2009) postulated that the physiologic functions of MED25 could be reduced in a dose-dependent manner by the variant due to increased competitive binding to additional interaction partners. Leal et al. (2018) found that affected members of the Costa Rican family with CMT2B2 carried a homozygous mutation in the PNKP gene (Q517X, 605610.0009), which maps to the same region as MED25. The MED25 and PNKP variants both fully segregated with the disorder in the family and were shown to be present on the same haplotype, suggesting an ancestral founder haplotype. (less)
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001980174.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001917627.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001931998.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Likely benign (Jul 15, 2020)	no assertion criteria provided Method: clinical testing	MED25-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004738785.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	Tip-toe gait Affected status: yes Allele origin: germline	Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino Accession: SCV002507277.2 First in ClinVar: May 16, 2022 Last updated: Jun 23, 2024	Publications: PubMed (1) PubMed: 37091313 Comment: Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, … (more) Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. (less) Clinical Features: Pes cavus (present) , Clinodactyly (present) , Brachydactyly (present) , Pectus excavatum (present) Age: 0-9 years Sex: male
not provided (-)	no classification provided Method: literature only	Charcot-Marie-Tooth disease type 2B2 Affected status: unknown Allele origin: unknown	ClinVar Staff, National Center for Biotechnology Information (NCBI) Accession: SCV000087015.2 First in ClinVar: Oct 01, 2013 Last updated: Oct 30, 2021 Comment: This SCV is no longer cited in the GeneReview (NBK1285).
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Comment:

Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
NGS-Panel Diagnosis Developed for the Differential Diagnosis of Idiopathic Toe Walking and Its Application for the Investigation of Possible Genetic Causes for the Gait Anomaly.	Pomarino D	Global medical genetics	2023	PMID: 37091313
The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25.	Leal A	Neurogenetics	2018	PMID: 30039206
Charcot-Marie-Tooth Neuropathy Type 2 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.	Adam MP	-	2016	PMID: 20301462
Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models.	Leal A	Neurogenetics	2009	PMID: 25488817
Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models.	Leal A	Neurogenetics	2009	PMID: 19290556
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MED25	-	-	-	-

Text-mined citations for rs145770066 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Feb 01, 2025

ClinVar Genomic variation as it relates to human health

NM_030973.4(MED25):c.1004C>T (p.Ala335Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs145770066 ...