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NM_000335.5(SCN5A):c.4891C>T (p.Arg1631Cys) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 5, 2020
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:
RCV002338764.1

Allele description

NM_000335.5(SCN5A):c.4891C>T (p.Arg1631Cys)

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.4891C>T (p.Arg1631Cys)
HGVS:
  • NC_000003.12:g.38551478G>A
  • NG_008934.1:g.103195C>T
  • NM_000335.5:c.4891C>TMANE SELECT
  • NM_001099404.2:c.4894C>T
  • NM_001099405.2:c.4840C>T
  • NM_001160160.2:c.4795C>T
  • NM_001160161.2:c.4732C>T
  • NM_001354701.2:c.4837C>T
  • NM_198056.3:c.4894C>T
  • NP_000326.2:p.Arg1631Cys
  • NP_001092874.1:p.Arg1632Cys
  • NP_001092875.1:p.Arg1614Cys
  • NP_001153632.1:p.Arg1599Cys
  • NP_001153633.1:p.Arg1578Cys
  • NP_001341630.1:p.Arg1613Cys
  • NP_932173.1:p.Arg1632Cys
  • NP_932173.1:p.Arg1632Cys
  • LRG_289t1:c.4894C>T
  • LRG_289:g.103195C>T
  • LRG_289p1:p.Arg1632Cys
  • NC_000003.11:g.38592969G>A
  • NM_198056.2:c.4894C>T
Protein change:
R1578C
Links:
dbSNP: rs878855292
NCBI 1000 Genomes Browser:
rs878855292
Molecular consequence:
  • NM_000335.5:c.4891C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099404.2:c.4894C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099405.2:c.4840C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160160.2:c.4795C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160161.2:c.4732C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354701.2:c.4837C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.3:c.4894C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002635766Ambry Genetics
criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)		Pathogenic
(Sep 5, 2020) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Enhanced fast-inactivated state stability of cardiac sodium channels by a novel voltage sensor SCN5A mutation, R1632C, as a cause of atypical Brugada syndrome.

Nakajima T, Kaneko Y, Saito A, Ota M, Iijima T, Kurabayashi M.

Heart Rhythm. 2015 Nov;12(11):2296-304. doi: 10.1016/j.hrthm.2015.05.032. Epub 2015 May 29.

PubMed [citation]
PMID:
26031372

An R1632C variant in the SCN5A gene causing Brugada syndrome.

García-Molina E, Sabater-Molina M, Muñoz C, Ruiz-Espejo F, Gimeno JR.

Mol Med Rep. 2016 Jun;13(6):4677-80. doi: 10.3892/mmr.2016.5100. Epub 2016 Apr 11.

PubMed [citation]
PMID:
27082542
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV002635766.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (5)

Description

The p.R1632C pathogenic mutation (also known as c.4894C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 4894. The arginine at codon 1632 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the DIV-S4 transmembrane region. This variant has been detected in unrelated probands with Brugada syndrome (BrS) and has shown some segregation with disease in families (Nakajima T et al. Heart Rhythm, 2015 Nov;12:2296-304; García-Molina E et al. Mol Med Rep, 2016 Jun;13:4677-80; Monasky MM et al. Front Physiol, 2019 May;10:666). Internal structural analysis indicates that the arginine impacted by this alteration is part of a highly conserved set of residues that generate a characteristic motif necessary to the function of voltage-sensing channels (Gandhi CS et al. J. Gen. Physiol., 2002 Oct;120:455-63; Starace DM et al. Nature, 2004 Feb;427:548-53). In vitro functional studies have indicated that this variant may impact channel kinetics, and a deep mutational scanning study categorized this alteration as a possible loss of function alteration (Nakajima T et al. Heart Rhythm, 2015 Nov;12:2296-304; Glazer AM et al. Circ Genom Precis Med, 2020 02;13:e002786). Other variants affecting this codon (p.R1632H, c.4895G>A and p.R1632L, c.4895G>T) have also been reported in association with arrhythmias, including Brugada syndrome (Benson DW et al. J. Clin. Invest. 2003;112:1019-28; Batchvarov VN et al. J Electrocardiol;44:308). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Apr 20, 2024