VCV003232117.3 - ClinVar

NM_000548.5(TSC2):c.2524C>G (p.Pro842Ala)

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.

(3)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000548.5(TSC2):c.2524C>G (p.Pro842Ala)

Variation ID: 3232117 Accession: VCV003232117.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.3 16: 2074368 (GRCh38) [ NCBI UCSC ] 16: 2124369 (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	May 1, 2024	Jan 25, 2025	Apr 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000548.5:c.2524C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000539.2:p.Pro842Ala	missense
NM_001077183.3:c.2524C>G	NP_001070651.1:p.Pro842Ala	missense
NM_001114382.3:c.2524C>G	NP_001107854.1:p.Pro842Ala	missense
NM_001318827.2:c.2413C>G	NP_001305756.1:p.Pro805Ala	missense
NM_001318829.2:c.2377C>G	NP_001305758.1:p.Pro793Ala	missense
NM_001318831.2:c.1924C>G	NP_001305760.1:p.Pro642Ala	missense
NM_001318832.2:c.2557C>G	NP_001305761.1:p.Pro853Ala	missense
NM_001363528.2:c.2524C>G	NP_001350457.1:p.Pro842Ala	missense
NM_001370404.1:c.2524C>G	NP_001357333.1:p.Pro842Ala	missense
NM_001370405.1:c.2524C>G	NP_001357334.1:p.Pro842Ala	missense
NM_001406663.1:c.2524C>G	NP_001393592.1:p.Pro842Ala	missense
NM_001406664.1:c.2524C>G	NP_001393593.1:p.Pro842Ala	missense
NM_001406665.1:c.2524C>G	NP_001393594.1:p.Pro842Ala	missense
NM_001406667.1:c.2614C>G	NP_001393596.1:p.Pro872Ala	missense
NM_001406668.1:c.2614C>G	NP_001393597.1:p.Pro872Ala	missense
NM_001406670.1:c.2413C>G	NP_001393599.1:p.Pro805Ala	missense
NM_001406671.1:c.2512C>G	NP_001393600.1:p.Pro838Ala	missense
NM_001406673.1:c.2512C>G	NP_001393602.1:p.Pro838Ala	missense
NM_001406675.1:c.2377C>G	NP_001393604.1:p.Pro793Ala	missense
NM_001406676.1:c.2377C>G	NP_001393605.1:p.Pro793Ala	missense
NM_001406677.1:c.2467C>G	NP_001393606.1:p.Pro823Ala	missense
NM_001406678.1:c.2413C>G	NP_001393607.1:p.Pro805Ala	missense
NM_001406679.1:c.2377C>G	NP_001393608.1:p.Pro793Ala	missense
NM_001406680.1:c.1924C>G	NP_001393609.1:p.Pro642Ala	missense
NM_001406681.1:c.2062C>G	NP_001393610.1:p.Pro688Ala	missense
NM_001406682.1:c.1924C>G	NP_001393611.1:p.Pro642Ala	missense
NM_001406683.1:c.1924C>G	NP_001393612.1:p.Pro642Ala	missense
NM_001406684.1:c.1924C>G	NP_001393613.1:p.Pro642Ala	missense
NM_001406685.1:c.1924C>G	NP_001393614.1:p.Pro642Ala	missense
NM_001406686.1:c.1924C>G	NP_001393615.1:p.Pro642Ala	missense
NM_001406687.1:c.1924C>G	NP_001393616.1:p.Pro642Ala	missense
NM_001406688.1:c.1924C>G	NP_001393617.1:p.Pro642Ala	missense
NM_001406689.1:c.1180C>G	NP_001393618.1:p.Pro394Ala	missense
NM_001406690.1:c.1180C>G	NP_001393619.1:p.Pro394Ala	missense
NM_001406691.1:c.1180C>G	NP_001393620.1:p.Pro394Ala	missense
NM_001406692.1:c.1180C>G	NP_001393621.1:p.Pro394Ala	missense
NM_001406693.1:c.1180C>G	NP_001393622.1:p.Pro394Ala	missense
NM_001406694.1:c.1180C>G	NP_001393623.1:p.Pro394Ala	missense
NM_001406695.1:c.1180C>G	NP_001393624.1:p.Pro394Ala	missense
NM_001406696.1:c.1180C>G	NP_001393625.1:p.Pro394Ala	missense
NM_001406697.1:c.1180C>G	NP_001393626.1:p.Pro394Ala	missense
NM_001406698.1:c.922C>G	NP_001393627.1:p.Pro308Ala	missense
NM_021055.3:c.2524C>G	NP_066399.2:p.Pro842Ala	missense
NR_176225.1:n.2674C>G		non-coding transcript variant
NR_176226.1:n.2853C>G		non-coding transcript variant
NR_176227.1:n.2853C>G		non-coding transcript variant
NR_176228.1:n.2674C>G		non-coding transcript variant
NR_176229.1:n.2634C>G		non-coding transcript variant
NC_000016.10:g.2074368C>G
NC_000016.9:g.2124369C>G
NG_005895.1:g.30063C>G
LRG_487:g.30063C>G
LRG_487t1:c.2524C>G	LRG_487p1:p.Pro842Ala

... more HGVS ... less HGVS

Protein change

P308A, P394A, P642A, P688A, P793A, P805A, P823A, P838A, P842A, P853A, P872A

Other names

Canonical SPDI

NC_000016.10:2074367:C:G

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.

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

Links

ClinGen: CA394277939 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.
TSC2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	10968	11169

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.
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Jan 31, 2024	RCV004520800.1
Isolated focal cortical dysplasia type II	Uncertain significance (1)	criteria provided, single submitter	Jan 12, 2024	RCV004573482.1
Isolated focal cortical dysplasia type II Lymphangiomyomatosis Tuberous sclerosis 2	Uncertain significance (1)	criteria provided, single submitter	Apr 26, 2024	RCV005015174.1

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.
Uncertain significance (Jan 31, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005036253.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: The p.P842A variant (also known as c.2524C>G), located in coding exon 21 of the TSC2 gene, results from a C to G substitution at nucleotide … (more) The p.P842A variant (also known as c.2524C>G), located in coding exon 21 of the TSC2 gene, results from a C to G substitution at nucleotide position 2524. The proline at codon 842 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Jan 12, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Isolated focal cortical dysplasia type II Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005054476.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Uncertain significance (Apr 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lymphangiomyomatosis Isolated focal cortical dysplasia type II Tuberous sclerosis 2 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV005645033.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025

Comment:

The p.P842A variant (also known as c.2524C>G), located in coding exon 21 of the TSC2 gene, results from a C to G substitution at nucleotide position 2524. The proline at codon 842 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Feb 01, 2025

ClinVar Genomic variation as it relates to human health

NM_000548.5(TSC2):c.2524C>G (p.Pro842Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...