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NM_000335.5(SCN5A):c.4996G>A (p.Val1666Ile) AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
May 30, 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:
RCV002336216.10

Allele description [Variation Report for NM_000335.5(SCN5A):c.4996G>A (p.Val1666Ile)]

NM_000335.5(SCN5A):c.4996G>A (p.Val1666Ile)

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.4996G>A (p.Val1666Ile)
HGVS:
  • NC_000003.12:g.38551373C>T
  • NG_008934.1:g.103300G>A
  • NM_000335.5:c.4996G>AMANE SELECT
  • NM_001099404.2:c.4999G>A
  • NM_001099405.2:c.4945G>A
  • NM_001160160.2:c.4900G>A
  • NM_001160161.2:c.4837G>A
  • NM_001354701.2:c.4942G>A
  • NM_198056.3:c.4999G>A
  • NP_000326.2:p.Val1666Ile
  • NP_001092874.1:p.Val1667Ile
  • NP_001092875.1:p.Val1649Ile
  • NP_001153632.1:p.Val1634Ile
  • NP_001153633.1:p.Val1613Ile
  • NP_001341630.1:p.Val1648Ile
  • NP_932173.1:p.Val1667Ile
  • NP_932173.1:p.Val1667Ile
  • LRG_289t1:c.4999G>A
  • LRG_289:g.103300G>A
  • LRG_289p1:p.Val1667Ile
  • NC_000003.11:g.38592864C>T
  • NM_001160160.1:c.4900G>A
  • NM_198056.2:c.4999G>A
Protein change:
V1613I
Links:
dbSNP: rs199473293
NCBI 1000 Genomes Browser:
rs199473293
Molecular consequence:
  • NM_000335.5:c.4996G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099404.2:c.4999G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099405.2:c.4945G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160160.2:c.4900G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160161.2:c.4837G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354701.2:c.4942G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.3:c.4999G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002640654Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(May 30, 2023) 		germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Effect of the antimalarial drug halofantrine in the long QT syndrome due to a mutation of the cardiac sodium channel gene SCN5A.

Piippo K, Holmström S, Swan H, Viitasalo M, Raatikka M, Toivonen L, Kontula K.

Am J Cardiol. 2001 Apr 1;87(7):909-11. No abstract available.

PubMed [citation]
PMID:
11274952

Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.

Tester DJ, Will ML, Haglund CM, Ackerman MJ.

Heart Rhythm. 2005 May;2(5):507-17.

PubMed [citation]
PMID:
15840476
See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV002640654.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

The p.V1667I variant (also known as c.4999G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 4999. The valine at codon 1667 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in individuals with long QT syndrome (LQTS), including segregating with disease in two families (Piippo K et al. Am. J. Cardiol., 2001 Apr;87:909-11; Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Hekkala AM et al. Europace, 2010 Sep;12:1296-301; Määttänen I et al. J Psychosom Res, 2011 Oct;71:245-9; Määttänen I et al. Stress Health, 2013 Apr;29:150-5; Amin AS et al. Int J Cardiol, 2018 Sep;266:128-132; Nakajima T et al. J Cardiovasc Electrophysiol, 2020 Aug;31:2107-2115). Additionally, in vitro analysis showed this alteration may impact protein function (Nakajima T et al. J Cardiovasc Electrophysiol, 2020 Aug;31:2107-2115). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Nov 24, 2024