NM_000335.5(SCN5A):c.3953G>T (p.Gly1318Val) AND Brugada syndrome (shorter-than-normal QT interval)

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 29, 2021
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:: RCV001553760.9

Allele description [Variation Report for NM_000335.5(SCN5A):c.3953G>T (p.Gly1318Val)]

NM_000335.5(SCN5A):c.3953G>T (p.Gly1318Val)

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.3953G>T (p.Gly1318Val)

HGVS:

NC_000003.12:g.38562422C>A
NG_008934.1:g.92251G>T
NM_000335.5:c.3953G>TMANE SELECT
NM_001099404.2:c.3956G>T
NM_001099405.2:c.3956G>T
NM_001160160.2:c.3953G>T
NM_001160161.2:c.3794G>T
NM_001354701.2:c.3953G>T
NM_198056.3:c.3956G>T
NP_000326.2:p.Gly1318Val
NP_001092874.1:p.Gly1319Val
NP_001092875.1:p.Gly1319Val
NP_001153632.1:p.Gly1318Val
NP_001153633.1:p.Gly1265Val
NP_001341630.1:p.Gly1318Val
NP_932173.1:p.Gly1319Val
NP_932173.1:p.Gly1319Val
LRG_289t1:c.3956G>T
LRG_289:g.92251G>T
LRG_289p1:p.Gly1319Val
NC_000003.11:g.38603913C>A
NM_198056.2:c.3956G>T
Q14524:p.Gly1319Val

Protein change:

G1265V

Links:

UniProtKB: Q14524#VAR_026375; dbSNP: rs199473220

NCBI 1000 Genomes Browser:

rs199473220

Molecular consequence:

NM_000335.5:c.3953G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.3956G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.3956G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.3953G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.3794G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.3953G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.3956G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Brugada syndrome (shorter-than-normal QT interval)
Identifiers:: MedGen: CN221547

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001774754	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jul 29, 2021)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 20129283, 21273195, 19843921, 19251209, 25179549, 26743238, 24573164, 30059973, 28790152, 17854786, 29759671 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001774754

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jul 29, 2021)

germline

clinical testing

PubMed (11)
[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

An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing.

Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, Brugada P, Fressart V, Guerchicoff A, Harris-Kerr C, Kamakura S, Kyndt F, Koopmann TT, Miyamoto Y, Pfeiffer R, Pollevick GD, Probst V, Zumhagen S, Vatta M, Towbin JA, Shimizu W, Schulze-Bahr E, et al.

Heart Rhythm. 2010 Jan;7(1):33-46. doi: 10.1016/j.hrthm.2009.09.069. Epub 2009 Oct 8.

PubMed [citation]

PMID:: 20129283
PMCID:: PMC2822446

Facilitatory and inhibitory effects of SCN5A mutations on atrial fibrillation in Brugada syndrome.

Amin AS, Boink GJ, Atrafi F, Spanjaart AM, Asghari-Roodsari A, Molenaar RJ, Ruijter JM, Wilde AA, Tan HL.

Europace. 2011 Jul;13(7):968-75. doi: 10.1093/europace/eur011. Epub 2011 Jan 26.

PubMed [citation]

PMID:: 21273195

See all PubMed Citations (11)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001774754.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

Variant summary: SCN5A c.3956G>T (p.Gly1319Val) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 238270 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in SCN5A causing Brugada Syndrome (4.2e-05 vs 0.00017), allowing no conclusion about variant significance. c.3956G>T has been reported in the literature in individuals affected with or suspected of Brugada Syndrome (example: Amin_2011, Casini_2007, Kapplinger_2010, Adler_2016) as well as in other in individuals of various cardiac phenotypes (example: Tadros_2017, Meregalli_2009). The variant was also reported in a proband and his son with dilated cardiomyopathy (Golbus_2014) as well as in a mother with reduced left ventricular ejection fraction and frequent ventricular ectopic beats and in her son with possible Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). The son also carried another LMNA variant (Hoorntje_2017). These data indicate that the variant is likely to be associated with disease. In an in vitro functional study, the variant was shown to enhance slow inactivation of SCN5A channel (Casini_2007). However, another in vitro study, co-expressing the wild-type channel and the variant report no reduction in channel current densities (Hoshi_2014). Five ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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: Nov 10, 2024

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