NM_000335.5(SCN5A):c.4928G>A (p.Arg1643His) AND Cardiovascular phenotype

Clinical significance:Pathogenic (Last evaluated: Nov 27, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000246905.2

Allele description [Variation Report for NM_000335.5(SCN5A):c.4928G>A (p.Arg1643His)]

NM_000335.5(SCN5A):c.4928G>A (p.Arg1643His)

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.4928G>A (p.Arg1643His)
Other names:
p.R1644H:CGC>CAC
HGVS:
  • NC_000003.12:g.38551441C>T
  • NG_008934.1:g.103232G>A
  • NM_000335.5:c.4928G>AMANE SELECT
  • NM_001099404.2:c.4931G>A
  • NM_001099405.2:c.4877G>A
  • NM_001160160.2:c.4832G>A
  • NM_001160161.2:c.4769G>A
  • NM_001354701.2:c.4874G>A
  • NM_198056.2:c.4931G>A
  • NM_198056.3:c.4931G>A
  • NP_000326.2:p.Arg1643His
  • NP_001092874.1:p.Arg1644His
  • NP_001092875.1:p.Arg1626His
  • NP_001153632.1:p.Arg1611His
  • NP_001153633.1:p.Arg1590His
  • NP_001341630.1:p.Arg1625His
  • NP_932173.1:p.Arg1644His
  • NP_932173.1:p.Arg1644His
  • LRG_289t1:c.4931G>A
  • LRG_289:g.103232G>A
  • LRG_289p1:p.Arg1644His
  • NC_000003.11:g.38592932C>T
  • Q14524:p.Arg1644His
Protein change:
R1590H; ARG1644HIS
Links:
UniProtKB: Q14524#VAR_001579; OMIM: 600163.0002; dbSNP: rs28937316
NCBI 1000 Genomes Browser:
rs28937316
Molecular consequence:
  • NM_000335.5:c.4928G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099404.2:c.4931G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099405.2:c.4877G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160160.2:c.4832G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160161.2:c.4769G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354701.2:c.4874G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.2:c.4931G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.3:c.4931G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000319611Ambry Geneticscriteria provided, single submitter
Pathogenic
(Nov 27, 2019)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Compound mutations: a common cause of severe long-QT syndrome.

Westenskow P, Splawski I, Timothy KW, Keating MT, Sanguinetti MC.

Circulation. 2004 Apr 20;109(15):1834-41. Epub 2004 Mar 29.

PubMed [citation]
PMID:
15051636

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 (5)

Details of each submission

From Ambry Genetics, SCV000319611.5

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

Description

The p.R1644H pathogenic mutation (also known as c.4931G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 4931. The arginine at codon 1644 is replaced by histidine. This mutation was originally detected in a mother and son affected with long QT syndrome (LQTS) in one family (Wang Q et al. Hum Mol Genet. 1995;4(9):1603-7). Other studies demonstrated disruption of inactivation in channels expressed in a human cell line and in Xenopus oocytes; p.R1644H showed sustained inward current predicted to account for the long QT defect, but findings suggested p.R1644H may be less severe than other alterations studied (Dumaine R et al. Circ Res. 1996;78(5):916-24; Wang DW et al. Proc Natl Acad Sci U.S.A. 1996;93(23):13200-5). In a study of compound mutations as a common cause of severe LQTS, p.R1644H was detected in the father and brother of a child with sudden death who also had a variant in the KCNE1 gene (Westenskow P et al. Circulation. 2004;109(15):1834-41). In a study of individuals with Brugada syndrome, another alteration of the same codon, p.R1644C (c.4930C>T), was reported in one individual and resulted in functionally abnormal protein (Frustaci A et al. Circulation. 2005;112(24):3680-7). Based on the supporting evidence, p.R1644H is interpreted as a disease-causing mutation.

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

Last Updated: Nov 27, 2021

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