VCV000067796.9 - ClinVar

NM_000335.5(SCN5A):c.3410A>C (p.Glu1137Ala)

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.

(4)

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_000335.5(SCN5A):c.3410A>C (p.Glu1137Ala)

Variation ID: 67796 Accession: VCV000067796.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 38576759 (GRCh38) [ NCBI UCSC ] 3: 38618250 (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	Jul 5, 2015	Feb 28, 2024	Oct 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000335.5:c.3410A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000326.2:p.Glu1137Ala	missense
NM_001099404.2:c.3413A>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001092874.1:p.Glu1138Ala	missense
NM_001099405.2:c.3413A>C	NP_001092875.1:p.Glu1138Ala	missense
NM_001160160.2:c.3410A>C	NP_001153632.1:p.Glu1137Ala	missense
NM_001160161.2:c.3251A>C	NP_001153633.1:p.Glu1084Ala	missense
NM_001354701.2:c.3410A>C	NP_001341630.1:p.Glu1137Ala	missense
NM_198056.3:c.3413A>C	NP_932173.1:p.Glu1138Ala	missense
NC_000003.12:g.38576759T>G
NC_000003.11:g.38618250T>G
NG_008934.1:g.77914A>C
LRG_289:g.77914A>C
LRG_289t1:c.3413A>C	LRG_289p1:p.Glu1138Ala

... more HGVS ... less HGVS

Protein change

E1137A, E1138A, E1084A

Other names

p.E1138A:GAG>GCG

Canonical SPDI

NC_000003.12:38576758:T: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA017144 dbSNP: rs199473198 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	3783	4225

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.
Congenital long QT syndrome	not provided (1)	no classification provided	-	RCV000058570.3
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 18, 2023	RCV000183036.5
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	Nov 14, 2021	RCV002477201.1

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 (Oct 18, 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: SCV000545075.6 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 19862833 Comment: This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1138 of the SCN5A protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1138 of the SCN5A protein (p.Glu1138Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 19862833). ClinVar contains an entry for this variant (Variation ID: 67796). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 (Nov 14, 2021)	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: SCV002786336.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Apr 12, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000235444.12 First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023	Comment: Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19862833)
not provided (-)	no classification provided Method: literature only	Congenital long QT syndrome Affected status: unknown Allele origin: germline	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust Accession: SCV000090090.3 First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016	Publications: PubMed (2) PubMed: 22581653‚ 19862833 Comment: This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19862833). This is a literature report, and does not necessarily … (more) This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19862833). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1138 of the SCN5A protein (p.Glu1138Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 19862833). ClinVar contains an entry for this variant (Variation ID: 67796). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 variant has been reported as associated with Long QT syndrome in the following publications (PMID:19862833). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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
The genetic basis of long QT and short QT syndromes: a mutation update.	Hedley PL	Human mutation	2009	PMID: 19862833

Text-mined citations for rs199473198 ...

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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000335.5(SCN5A):c.3410A>C (p.Glu1137Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199473198 ...