NM_000335.5(SCN5A):c.2314G>A (p.Asp772Asn) AND Cardiac arrhythmia

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 18, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001841598.13

Allele description [Variation Report for NM_000335.5(SCN5A):c.2314G>A (p.Asp772Asn)]

NM_000335.5(SCN5A):c.2314G>A (p.Asp772Asn)

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.2314G>A (p.Asp772Asn)

HGVS:

NC_000003.12:g.38587522C>T
NG_008934.1:g.67151G>A
NM_000335.5:c.2314G>AMANE SELECT
NM_001099404.2:c.2314G>A
NM_001099405.2:c.2314G>A
NM_001160160.2:c.2314G>A
NM_001160161.2:c.2314G>A
NM_001354701.2:c.2314G>A
NM_198056.3:c.2314G>A
NP_000326.2:p.Asp772Asn
NP_000326.2:p.Asp772Asn
NP_001092874.1:p.Asp772Asn
NP_001092875.1:p.Asp772Asn
NP_001153632.1:p.Asp772Asn
NP_001153633.1:p.Asp772Asn
NP_001153633.1:p.Asp772Asn
NP_001341630.1:p.Asp772Asn
NP_932173.1:p.Asp772Asn
NP_932173.1:p.Asp772Asn
LRG_289t1:c.2314G>A
LRG_289t2:c.2314G>A
LRG_289:g.67151G>A
LRG_289p1:p.Asp772Asn
LRG_289p2:p.Asp772Asn
NC_000003.11:g.38629013C>T
NM_000335.4:c.2314G>A
NM_001160161.1:c.2314G>A
NM_198056.2:c.2314G>A
Q14524:p.Asp772Asn
c.2314G>A

Protein change:

D772N

Links:

UniProtKB: Q14524#VAR_074382; dbSNP: rs199473157

NCBI 1000 Genomes Browser:

rs199473157

Molecular consequence:

NM_000335.5:c.2314G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.2314G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.2314G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.2314G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.2314G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.2314G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.2314G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Cardiac arrhythmia
Synonyms:: Cardiac rhythm disease
Identifiers:: EFO: EFO_0004269; MONDO: MONDO:0007263; MedGen: C0003811; Human Phenotype Ontology: HP:0011675

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001344275	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 2, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 19716085, 20129283, 23571586, 32268277, 32893267, 34935411, 25741868
SCV004823456	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 18, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 19716085, 20129283, 23571586, 32268277, 32893267, 34935411, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001344275

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 2, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004823456

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 18, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	5	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test.

Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ.

Heart Rhythm. 2009 Sep;6(9):1297-303. doi: 10.1016/j.hrthm.2009.05.021. Epub 2009 Jun 23.

PubMed [citation]

PMID:: 19716085
PMCID:: PMC3049907

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

See all PubMed Citations (7)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001344275.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant replaces aspartic acid with asparagine at codon 772 of the SCN5A protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved transmembrane domain (a.a. 718-938). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). Functional studies have reported conflicting results, with one study showing this variant has shorter inactivation time constants compared to wild type controls, and the other study showing the variant does not affect the sodium channel function (PMID: 23571586, 32268277). This variant has been reported in an individual referred for long QT syndrome testing (PMID: 19716085) and in an individual referred for Brugada testing (PMID: 20129283). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 34935411). This variant has been identified in 5/249248 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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

From All of Us Research Program, National Institutes of Health, SCV004823456.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (7)

Description

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		5	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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