NM_000335.5(SCN5A):c.1844G>A (p.Gly615Glu) AND Cardiovascular phenotype

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 25, 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:: RCV000622256.14

Allele description [Variation Report for NM_000335.5(SCN5A):c.1844G>A (p.Gly615Glu)]

NM_000335.5(SCN5A):c.1844G>A (p.Gly615Glu)

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.1844G>A (p.Gly615Glu)

Other names:

p.G615E:GGA>GAA

HGVS:

NC_000003.12:g.38603758C>T
NG_008934.1:g.50915G>A
NM_000335.5:c.1844G>AMANE SELECT
NM_001099404.2:c.1844G>A
NM_001099405.2:c.1844G>A
NM_001160160.2:c.1844G>A
NM_001160161.2:c.1844G>A
NM_001354701.2:c.1844G>A
NM_198056.3:c.1844G>A
NP_000326.2:p.Gly615Glu
NP_000326.2:p.Gly615Glu
NP_001092874.1:p.Gly615Glu
NP_001092875.1:p.Gly615Glu
NP_001153632.1:p.Gly615Glu
NP_001153633.1:p.Gly615Glu
NP_001341630.1:p.Gly615Glu
NP_932173.1:p.Gly615Glu
NP_932173.1:p.Gly615Glu
LRG_289t1:c.1844G>A
LRG_289t2:c.1844G>A
LRG_289:g.50915G>A
LRG_289p1:p.Gly615Glu
LRG_289p2:p.Gly615Glu
NC_000003.11:g.38645249C>T
NM_000335.4:c.1844G>A
NM_198056.2:c.1844G>A
Q14524:p.Gly615Glu

Protein change:

G615E

Links:

UniProtKB: Q14524#VAR_026358; dbSNP: rs12720452

NCBI 1000 Genomes Browser:

rs12720452

Molecular consequence:

NM_000335.5:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000737801	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Aug 25, 2023)	germline	clinical testing	PubMed (19) [See all records that cite these PMIDs] 11997281, 18071069, 19716085, 23631430, 24055113, 24613995, 24713084, 25637381, 25650408, 27153395, 27435932, 28412158, 29728395, 29874177, 30193851, 31262209, 31737537, 32516855, 34461752 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000737801

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Aug 25, 2023)

germline

clinical testing

PubMed (19)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes.

Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC, Hohnloser SH, Shimizu W, Schwartz PJ, Stanton M, Murray KT, Norris K, George AL Jr, Roden DM.

Circulation. 2002 Apr 23;105(16):1943-8.

PubMed [citation]

PMID:: 11997281

Cardiac sodium channel gene variants and sudden cardiac death in women.

Albert CM, Nam EG, Rimm EB, Jin HW, Hajjar RJ, Hunter DJ, MacRae CA, Ellinor PT.

Circulation. 2008 Jan 1;117(1):16-23. Epub 2007 Dec 10.

PubMed [citation]

PMID:: 18071069

See all PubMed Citations (19)

Details of each submission

From Ambry Genetics, SCV000737801.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (19)

Description

The p.G615E variant (also known as c.1844G>A), located in coding exon 11 of the SCN5A gene, results from a G to A substitution at nucleotide position 1844. The glycine at codon 615 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in subjects with acquired long QT syndrome, long QT syndrome, Brugada syndrome, and dilated cardiomyopathy; however, in some cases, clinical details were limited and/or additional cardiac variants were detected (Yang P et al. Circulation, 2002 Apr;105:1943-8; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Le Scouarnec S et al. Hum. Mol. Genet., 2015 May;24:2757-63; Hawley MH et al. Hum Mutat, 2020 09;41:1577-1587). It has also been reported in sudden death and stillbirth cohorts (Albert CM et al. Circulation, 2008 Jan;117:16-23; Methner DN et al. Genome Res., 2016 Sep;26:1170-7; Munroe PB et al. Circ Genom Precis Med, 2018 01;11:e001817). This variant has also been seen in exome cohorts, as well as an irritable bowel syndrome cohort (Dorschner MO et al. Am J Hum Genet. 2013;93(4):631-40; Beyder A et al. Gastroenterology, 2014 Jun;146:1659-68; Amendola LM et al. Genome Res. 2015;25(3):305-15; Maxwell KN et al. Am. J. Hum. Genet., 2016 May;98:801-17). Functional studies have shown little or no impact on voltage function, but possible mechanosensitivity effects; however, the clinical relevance of these findings is uncertain (Yang P et al. Circulation, 2002 Apr;105:1943-8; Albert CM et al. Circulation, 2008 Jan;117:16-23; Strege PR et al. Channels (Austin), 2019 12;13:287-298). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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