NM_000335.5(SCN5A):c.1127G>A (p.Arg376His) AND Brugada syndrome

Clinical significance:Pathogenic (Last evaluated: Sep 11, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000058396.5

Allele description [Variation Report for NM_000335.5(SCN5A):c.1127G>A (p.Arg376His)]

NM_000335.5(SCN5A):c.1127G>A (p.Arg376His)

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.1127G>A (p.Arg376His)
Other names:
p.R376H:CGC>CAC
HGVS:
  • NC_000003.12:g.38606682C>T
  • NG_008934.1:g.47991G>A
  • NM_000335.5:c.1127G>AMANE SELECT
  • NM_001099404.2:c.1127G>A
  • NM_001099405.2:c.1127G>A
  • NM_001160160.2:c.1127G>A
  • NM_001160161.2:c.1127G>A
  • NM_001354701.2:c.1127G>A
  • NM_198056.2:c.1127G>A
  • NM_198056.3:c.1127G>A
  • NP_000326.2:p.Arg376His
  • NP_001092874.1:p.Arg376His
  • NP_001092875.1:p.Arg376His
  • NP_001153632.1:p.Arg376His
  • NP_001153633.1:p.Arg376His
  • NP_001341630.1:p.Arg376His
  • NP_932173.1:p.Arg376His
  • NP_932173.1:p.Arg376His
  • LRG_289t1:c.1127G>A
  • LRG_289:g.47991G>A
  • LRG_289p1:p.Arg376His
  • NC_000003.11:g.38648173C>T
  • Q14524:p.Arg376His
Protein change:
R376H
Links:
UniProtKB: Q14524#VAR_055169; dbSNP: rs199473101
NCBI 1000 Genomes Browser:
rs199473101
Molecular consequence:
  • NM_000335.5:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099404.2:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099405.2:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160160.2:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160161.2:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354701.2:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.2:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.3:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Brugada syndrome
Synonyms:
Sudden unexpected nocturnal death syndrome; Sudden unexplained nocturnal death syndrome; Sudden Unexplained Death Syndrome; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015263; MedGen: C1142166; OMIM: PS601144

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000089916Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trustno assertion providednot providedgermlineliterature only

PubMed (5)
[See all records that cite these PMIDs]

SCV000760186Invitaecriteria provided, single submitter
Pathogenic
(Sep 11, 2020)
germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, literature only

Citations

PubMed

Paralogous annotation of disease-causing variants in long QT syndrome genes.

Ware JS, Walsh R, Cunningham F, Birney E, Cook SA.

Hum Mutat. 2012 Aug;33(8):1188-1191. doi: 10.1002/humu.22114. Epub 2012 Jun 7.

PubMed [citation]
PMID:
22581653
PMCID:
PMC4640174

Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome.

Frustaci A, Priori SG, Pieroni M, Chimenti C, Napolitano C, Rivolta I, Sanna T, Bellocci F, Russo MA.

Circulation. 2005 Dec 13;112(24):3680-7.

PubMed [citation]
PMID:
16344400
See all PubMed Citations (12)

Details of each submission

From Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust, SCV000089916.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (5)

Description

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:15851228;PMID:16344400;PMID:20129283;PMID:18378609). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000760186.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)

Description

This sequence change replaces arginine with histidine at codon 376 of the SCN5A protein (p.Arg376His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in the literature segregating with disease in one family (PMID: 15851228), in several individuals affected with Brugada syndrome (PMID: 16344400, 28341781), atrial fibrillation (PMID: 18378609), hypertrophic cardiomyopathy (PMID: 27930701), in individuals referred for Brugada genetic testing (PMID: 20129283), and in individuals who suffered sudden unexplained death (PMID: 25194972, 23671135). ClinVar contains an entry for this variant (Variation ID: 67639). Experimental studies have shown that this missense change causes a reduction of the current density consistent with a Brugada syndrome pattern (PMID: 15851228, 24295898, 21840964). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 20, 2021

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