VCV000582721.16 - ClinVar

NM_000335.5(SCN5A):c.5792C>T (p.Ala1931Val)

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.

(6)

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(4); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000335.5(SCN5A):c.5792C>T (p.Ala1931Val)

Variation ID: 582721 Accession: VCV000582721.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 38550577 (GRCh38) [ NCBI UCSC ] 3: 38592068 (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 10, 2018	May 1, 2024	Feb 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000335.5:c.5792C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000326.2:p.Ala1931Val	missense
NM_001099404.2:c.5795C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001092874.1:p.Ala1932Val	missense
NM_001099405.2:c.5741C>T	NP_001092875.1:p.Ala1914Val	missense
NM_001160160.2:c.5696C>T	NP_001153632.1:p.Ala1899Val	missense
NM_001160161.2:c.5633C>T	NP_001153633.1:p.Ala1878Val	missense
NM_001354701.2:c.5738C>T	NP_001341630.1:p.Ala1913Val	missense
NM_198056.3:c.5795C>T	NP_932173.1:p.Ala1932Val	missense
NC_000003.12:g.38550577G>A
NC_000003.11:g.38592068G>A
NG_008934.1:g.104096C>T
LRG_289:g.104096C>T
LRG_289t1:c.5795C>T	LRG_289p1:p.Ala1932Val

... more HGVS ... less HGVS

Protein change

A1931V, A1932V, A1878V, A1899V, A1913V, A1914V

Other names

Canonical SPDI

NC_000003.12:38550576:G:A

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00003

The Genome Aggregation Database (gnomAD) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00004

Exome Aggregation Consortium (ExAC) 0.00007

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

dbSNP: rs371194826 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.
SCN5A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3793	4237

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.
Primary dilated cardiomyopathy	Likely benign (1)	criteria provided, single submitter	May 8, 2019	RCV000852962.9
Atrial fibrillation, familial, 10 Brugada syndrome 1 Dilated cardiomyopathy 1E Long QT syndrome 3 Progressive familial heart block, type 1A SUDDEN INFANT DEATH SYNDROME Sick sinus syndrome 1 Ventricular fibrillation, paroxysmal familial, type 1	Uncertain significance (1)	criteria provided, single submitter	Oct 31, 2018	RCV000764501.10
Cardiac arrhythmia	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 5, 2024	RCV001841875.13
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	May 22, 2023	RCV002352218.10
not provided	Uncertain significance (1)	criteria provided, single submitter	Aug 27, 2023	RCV003540842.2

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.
Uncertain significance (Aug 27, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000835934.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 28492532‚ 31983221 Comment: This variant is present in population databases (rs371194826, gnomAD 0.03%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral … (more) This variant is present in population databases (rs371194826, gnomAD 0.03%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1932 of the SCN5A protein (p.Ala1932Val). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 582721). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Progressive familial heart block, type 1A SUDDEN INFANT DEATH SYNDROME Brugada syndrome 1 Dilated cardiomyopathy 1E Ventricular fibrillation, paroxysmal familial, type 1 Long QT syndrome 3 Sick sinus syndrome 1 Atrial fibrillation, familial, 10 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000895572.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Likely benign (May 08, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy Affected status: yes Allele origin: germline	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego Accession: SCV000995711.1 First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019	Number of individuals with the variant: 1
Uncertain significance (Mar 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiac arrhythmia Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001340230.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 31983221 Comment: This missense variant replaces alanine with valine at codon 1932 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces alanine with valine at codon 1932 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant was identified in an individual affected with dilated cardiomyopathy (PMID: 31983221). This variant has been identified in 10/249044 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain Significance (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiac arrhythmia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004816621.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (1) PubMed: 31983221 Comment: This missense variant replaces alanine with valine at codon 1932 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces alanine with valine at codon 1932 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant was identified in an individual affected with dilated cardiomyopathy (PMID: 31983221). This variant has been identified in 10/249044 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Number of individuals with the variant: 5 Zygosity: Single Heterozygote
Likely benign (May 22, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002648957.3 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)

Comment:

This variant is present in population databases (rs371194826, gnomAD 0.03%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1932 of the SCN5A protein (p.Ala1932Val). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 582721). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

This missense variant replaces alanine with valine at codon 1932 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant was identified in an individual affected with dilated cardiomyopathy (PMID: 31983221). This variant has been identified in 10/249044 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy.	Mazzarotto F	Circulation	2020	PMID: 31983221

Text-mined citations for rs371194826 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000335.5(SCN5A):c.5792C>T (p.Ala1931Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs371194826 ...