NM_000335.5(SCN5A):c.6043G>A (p.Val2015Met) AND Cardiovascular phenotype

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 24, 2024
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:: RCV002354484.11

Allele description [Variation Report for NM_000335.5(SCN5A):c.6043G>A (p.Val2015Met)]

NM_000335.5(SCN5A):c.6043G>A (p.Val2015Met)

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.6043G>A (p.Val2015Met)

HGVS:

NC_000003.12:g.38550326C>T
NG_008934.1:g.104347G>A
NM_000335.5:c.6043G>AMANE SELECT
NM_001099404.2:c.6046G>A
NM_001099405.2:c.5992G>A
NM_001160160.2:c.5947G>A
NM_001160161.2:c.5884G>A
NM_001354701.2:c.5989G>A
NM_198056.3:c.6046G>A
NP_000326.2:p.Val2015Met
NP_001092874.1:p.Val2016Met
NP_001092874.1:p.Val2016Met
NP_001092875.1:p.Val1998Met
NP_001153632.1:p.Val1983Met
NP_001153633.1:p.Val1962Met
NP_001341630.1:p.Val1997Met
NP_932173.1:p.Val2016Met
NP_932173.1:p.Val2016Met
LRG_289t1:c.6046G>A
LRG_289t3:c.6046G>A
LRG_289:g.104347G>A
LRG_289p1:p.Val2016Met
LRG_289p3:p.Val2016Met
NC_000003.11:g.38591817C>T
NM_001099404.1:c.6046G>A
NM_198056.2:c.6046G>A

Protein change:

V1962M

Links:

dbSNP: rs762981322

NCBI 1000 Genomes Browser:

rs762981322

Molecular consequence:

NM_000335.5:c.6043G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.6046G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.5992G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.5947G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.5884G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.5989G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.6046G>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
SCV002656729	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 24, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 24895455, 26282245, 27650965, 28069705, 29907873, 30662450, 30847666, 33083013, 35932045 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002656729

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 24, 2024)

germline

clinical testing

PubMed (9)
[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

PDZ domain-binding motif regulates cardiomyocyte compartment-specific NaV1.5 channel expression and function.

Shy D, Gillet L, Ogrodnik J, Albesa M, Verkerk AO, Wolswinkel R, Rougier JS, Barc J, Essers MC, Syam N, Marsman RF, van Mil AM, Rotman S, Redon R, Bezzina CR, Remme CA, Abriel H.

Circulation. 2014 Jul 8;130(2):147-60. doi: 10.1161/CIRCULATIONAHA.113.007852. Epub 2014 Jun 3.

PubMed [citation]

PMID:: 24895455

Cardiac sodium channel mutation associated with epinephrine-induced QT prolongation and sinus node dysfunction.

Chen J, Makiyama T, Wuriyanghai Y, Ohno S, Sasaki K, Hayano M, Harita T, Nishiuchi S, Yuta Yamamoto, Ueyama T, Shimizu A, Horie M, Kimura T.

Heart Rhythm. 2016 Jan;13(1):289-98. doi: 10.1016/j.hrthm.2015.08.021. Epub 2015 Aug 14.

PubMed [citation]

PMID:: 26282245

See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV002656729.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The p.V2016M variant (also known as c.6046G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 6046. The valine at codon 2016 is replaced by methionine, an amino acid with highly similar properties. This alteration has been detected in individuals with long QT syndrome (LQT), Brugada syndrome (BrS), arrhythmogenic right ventricular cardiomyopathy (ARVC), sudden death, hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (HCM); however, clinical details were often limited and co-occurring variants were reported in some cases (Shy D et al. Circulation, 2014 Jul;130:147-60; Chen J et al. Heart Rhythm, 2016 Jan;13:289-98; Christiansen SL et al. Eur J Hum Genet, 2016 12;24:1797-1802; Te Riele AS et al. Cardiovasc Res, 2017 01;113:102-111; Hayashi T et al. J Hum Genet, 2018 Sep;63:989-996; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). Studies of the effect of this variant on channel function were contradictory, with both gain and loss of function reported by different investigators (Shy D et al. Circulation, 2014 Jul;130:147-60; Chen J et al. Heart Rhythm, 2016 Jan;13:289-98). This variant has also been reported in an ostensibly healthy cohort (Bajaj A et al. Hum Genomics, 2022 Aug;16:30). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited 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 26, 2024

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