VCV001343340.2 - ClinVar

NM_014171.6(CRIPT):c.7_8del (p.Cys3fs)

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.

(2)

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.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_014171.6(CRIPT):c.7_8del (p.Cys3fs)

Variation ID: 1343340 Accession: VCV001343340.2

Type and length

Microsatellite, 2 bp

Location

Cytogenetic: 2p21 2: 46617286-46617287 (GRCh38) [ NCBI UCSC ] 2: 46844425-46844426 (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	Sep 10, 2022	May 7, 2024	Mar 9, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_014171.6:c.7_8del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_054890.1:p.Cys3fs	frameshift
NC_000002.12:g.46617287TG[1]
NC_000002.11:g.46844426TG[1]
NG_034144.1:g.5116TG[1]

Protein change

C3fs

Other names

p.Cys3Argfs*

Canonical SPDI

NC_000002.12:46617285:GTGTG:GTG

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

loss_of_function_variant; Sequence Ontology [ SO:0002054]

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.

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

Links

OMIM: 604594.0005 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.
CRIPT		-	-	GRCh38 GRCh37	73	93

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.
Rothmund-Thomson syndrome, type 3	Pathogenic (2)	criteria provided, single submitter	Mar 9, 2022	RCV002281649.3

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.
Pathogenic (Mar 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rothmund-Thomson syndrome, type 3 (Autosomal recessive inheritance) Affected status: no, yes Allele origin: germline	Hacettepe Pediatric Genetics Laboratory, Hacettepe University Accession: SCV002102829.1 First in ClinVar: Sep 10, 2022 Last updated: Sep 10, 2022	Comment: Sequencing analysis of the CRIPT gene identified a novel homozygous frameshift variant (c.7_8delTG; p.Cys3Argfs4) in a patient whose clinical features were compatible with Short Stature … (more) Sequencing analysis of the CRIPT gene identified a novel homozygous frameshift variant (c.7_8delTG; p.Cys3Argfs4) in a patient whose clinical features were compatible with Short Stature with Microcephaly and Distinctive Facies. This variant has not been reported in 1000 Genomes Project database and there is only one heterozygous individual in gnomAD data (allele frequency= 0.0000063). This change was classified as “pathogenic” according to the ACMG guidelines. (less) Observation 1: Number of individuals with the variant: 2 Number of families with the variant: 1 Zygosity: Single Heterozygote Age: 20-29 years Sex: mixed Ethnicity/Population group: Turkish Geographic origin: Turkey Observation 2: Clinical Features: Microcephaly (present) , Abnormality of retinal pigmentation (present) , Talipes equinovalgus (present) , Global developmental delay (present) , Hypopigmentation of the skin (present) , Craniosynostosis … (more) Microcephaly (present) , Abnormality of retinal pigmentation (present) , Talipes equinovalgus (present) , Global developmental delay (present) , Hypopigmentation of the skin (present) , Craniosynostosis syndrome (present) , Keratosis pilaris (present) (less) Zygosity: Homozygote Age: 0-9 years Sex: male Ethnicity/Population group: Turkish Geographic origin: Turkey
Pathogenic (Apr 29, 2024)	no assertion criteria provided Method: literature only	ROTHMUND-THOMSON SYNDROME, TYPE 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV005038927.1 First in ClinVar: May 07, 2024 Last updated: May 07, 2024	Publications: PubMed (1) PubMed: 36630262 Comment on evidence: In a Turkish boy with short stature, failure to thrive, dysmorphic facial features, alopecia, and reticular hypopigmented skin lesions (RTS3; 615789), who died at 4 … (more) In a Turkish boy with short stature, failure to thrive, dysmorphic facial features, alopecia, and reticular hypopigmented skin lesions (RTS3; 615789), who died at 4 years of age due to a severe pulmonary infection with respiratory insufficiency, Akalin et al. (2023) identified homozygosity for a 2-bp deletion (c.7_8del, NM_014171.6) in exon 1 of the CRIPT gene, causing a frameshift predicted to result in a premature termination codon (Cys3ArgfsTer4). His parents were heterozygous for the mutation, which was not found in the ExAC or 1000 Genomes Project databases; however, 1 allele was present in the European (non-Finnish) population of the gnomAD database. (less)

Comment:

Sequencing analysis of the CRIPT gene identified a novel homozygous frameshift variant (c.7_8delTG; p.Cys3Argfs*4) in a patient whose clinical features were compatible with Short Stature with Microcephaly and Distinctive Facies. This variant has not been reported in 1000 Genomes Project database and there is only one heterozygous individual in gnomAD data (allele frequency= 0.0000063). This change was classified as “pathogenic” according to the ACMG guidelines.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
loss_of_function_variant (SO:0002054)			Hacettepe Pediatric Genetics Laboratory, Hacettepe University Accession: SCV002102829.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A novel biallelic CRIPT variant in a patient with short stature, microcephaly, and distinctive facial features.	Akalın A	American journal of medical genetics. Part A	2023	PMID: 36630262

Text-mined citations for this variant ...

Record last updated Jul 15, 2024

ClinVar Genomic variation as it relates to human health

NM_014171.6(CRIPT):c.7_8del (p.Cys3fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...