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NM_000335.5(SCN5A):c.3781G>A (p.Gly1261Ser) AND Cardiac arrhythmia

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
May 4, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003996086.2

Allele description [Variation Report for NM_000335.5(SCN5A):c.3781G>A (p.Gly1261Ser)]

NM_000335.5(SCN5A):c.3781G>A (p.Gly1261Ser)

Gene:
SCN5A:sodium voltage-gated channel alpha subunit 5 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p22.2
Genomic location:
Preferred name:
NM_000335.5(SCN5A):c.3781G>A (p.Gly1261Ser)
HGVS:
  • NC_000003.12:g.38566465C>T
  • NG_008934.1:g.88208G>A
  • NM_000335.5:c.3781G>AMANE SELECT
  • NM_001099404.2:c.3784G>A
  • NM_001099405.2:c.3784G>A
  • NM_001160160.2:c.3781G>A
  • NM_001160161.2:c.3622G>A
  • NM_001354701.2:c.3781G>A
  • NM_198056.3:c.3784G>A
  • NP_000326.2:p.Gly1261Ser
  • NP_000326.2:p.Gly1261Ser
  • NP_001092874.1:p.Gly1262Ser
  • NP_001092875.1:p.Gly1262Ser
  • NP_001153632.1:p.Gly1261Ser
  • NP_001153633.1:p.Gly1208Ser
  • NP_001341630.1:p.Gly1261Ser
  • NP_932173.1:p.Gly1262Ser
  • NP_932173.1:p.Gly1262Ser
  • LRG_289t1:c.3784G>A
  • LRG_289t2:c.3781G>A
  • LRG_289:g.88208G>A
  • LRG_289p1:p.Gly1262Ser
  • LRG_289p2:p.Gly1261Ser
  • NC_000003.11:g.38607956C>T
  • NM_000335.4:c.3781G>A
  • NM_198056.2:c.3784G>A
Protein change:
G1208S; GLY1262SER
Links:
OMIM: 600163.0032; dbSNP: rs137854616
NCBI 1000 Genomes Browser:
rs137854616
Molecular consequence:
  • NM_000335.5:c.3781G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099404.2:c.3784G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099405.2:c.3784G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160160.2:c.3781G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160161.2:c.3622G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354701.2:c.3781G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.3:c.3784G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

Condition(s)

Name:
Cardiac arrhythmia
Synonyms:
Cardiac rhythm disease
Identifiers:
EFO: EFO_0004269; MONDO: MONDO:0007263; MedGen: C0003811; Human Phenotype Ontology: HP:0011675

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004831376All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(May 4, 2023) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown2not providednot provided108544not providedclinical testing

Citations

PubMed

Genetic analysis of the cardiac sodium channel gene SCN5A in Koreans with Brugada syndrome.

Shin DJ, Jang Y, Park HY, Lee JE, Yang K, Kim E, Bae Y, Kim J, Kim J, Kim SS, Lee MH, Chahine M, Yoon SK.

J Hum Genet. 2004;49(10):573-578. doi: 10.1007/s10038-004-0182-z. Epub 2004 Aug 26.

PubMed [citation]
PMID:
15338453

An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing.

Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, Brugada P, Fressart V, Guerchicoff A, Harris-Kerr C, Kamakura S, Kyndt F, Koopmann TT, Miyamoto Y, Pfeiffer R, Pollevick GD, Probst V, Zumhagen S, Vatta M, Towbin JA, Shimizu W, Schulze-Bahr E, et al.

Heart Rhythm. 2010 Jan;7(1):33-46. doi: 10.1016/j.hrthm.2009.09.069. Epub 2009 Oct 8.

PubMed [citation]
PMID:
20129283
PMCID:
PMC2822446
See all PubMed Citations (4)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004831376.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (4)

Description

This missense variant replaces glycine with serine at codon 1262 of the SCN5A protein. This variant is also known as c.3781G>A (p.Gly1261Ser) based on a different transcript NM_000335.5. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with Brugada syndrome including two who were from the same family (PMID: 15338453, 20129283), two individuals affected with dilated cardiomyopathy and one individual with hypertrophic cardiomyopathy (PMID: 27554632), and in another individual affected with noncompaction cardiomyopathy and atrial fibrillation (Van Waning 2020, dissertation, Erasmus University Rotterdam). This variant has been identified in 8/282850 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided2not providednot providednot provided

Last Updated: Oct 8, 2024