NM_000335.5(SCN5A):c.2923C>T (p.Arg975Trp) AND Cardiac arrhythmia

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 11, 2024
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:: RCV001842321.13

Allele description [Variation Report for NM_000335.5(SCN5A):c.2923C>T (p.Arg975Trp)]

NM_000335.5(SCN5A):c.2923C>T (p.Arg975Trp)

Genes:

LOC110121269:VISTA enhancer hs2177 [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.2923C>T (p.Arg975Trp)

HGVS:

NC_000003.12:g.38581236G>A
NG_008934.1:g.73437C>T
NG_053884.1:g.2975G>A
NM_000335.5:c.2923C>TMANE SELECT
NM_001099404.2:c.2923C>T
NM_001099405.2:c.2923C>T
NM_001160160.2:c.2923C>T
NM_001160161.2:c.2923C>T
NM_001354701.2:c.2923C>T
NM_198056.3:c.2923C>T
NP_000326.2:p.Arg975Trp
NP_001092874.1:p.Arg975Trp
NP_001092875.1:p.Arg975Trp
NP_001153632.1:p.Arg975Trp
NP_001153633.1:p.Arg975Trp
NP_001341630.1:p.Arg975Trp
NP_932173.1:p.Arg975Trp
NP_932173.1:p.Arg975Trp
LRG_289t1:c.2923C>T
LRG_289:g.73437C>T
LRG_289p1:p.Arg975Trp
NC_000003.11:g.38622727G>A
NM_000335.5:c.2923C>T
NM_198056.2:c.2923C>T

Protein change:

R975W

Links:

dbSNP: rs41311135

NCBI 1000 Genomes Browser:

rs41311135

Molecular consequence:

NM_000335.5:c.2923C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.2923C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.2923C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.2923C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.2923C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.2923C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.2923C>T - 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

Recent activity

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Bacillus sp. MOLA 661 partial 16S rRNA gene, culture collection MOLA:661
Bacillus sp. MOLA 661 partial 16S rRNA gene, culture collection MOLA:661
gi|187293564|emb|AM990774.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001346806	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 1, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15851227, 19322600, 19841300, 20129283, 26669661, 27816319, 32145446, 25741868
SCV004822745	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15851227, 19322600, 19841300, 20129283, 26669661, 27816319, 32145446, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001346806

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 1, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV004822745

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 11, 2024)

germline

clinical testing

PubMed (8)
[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	6	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing.

Ackerman MJ, Splawski I, Makielski JC, Tester DJ, Will ML, Timothy KW, Keating MT, Jones G, Chadha M, Burrow CR, Stephens JC, Xu C, Judson R, Curran ME.

Heart Rhythm. 2004 Nov;1(5):600-7.

PubMed [citation]

PMID:: 15851227

Contribution of long-QT syndrome genetic variants in sudden infant death syndrome.

Millat G, Kugener B, Chevalier P, Chahine M, Huang H, Malicier D, Rodriguez-Lafrasse C, Rousson R.

Pediatr Cardiol. 2009 May;30(4):502-9. doi: 10.1007/s00246-009-9417-2. Epub 2009 Mar 26.

PubMed [citation]

PMID:: 19322600

See all PubMed Citations (8)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001346806.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This missense variant replaces arginine with tryptophan at codon 975 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in the literature in two related individuals affected with long QT syndrome (PMID: 26669661, 27816319), in an individual referred for long QT syndrome genetic testing (PMID: 20129283), and in two infants affected with sudden death (PMID: 19322600, 32145446). This variant has also been observed in healthy control individuals (PMID: 15851227, 19841300). This variant has been identified in 8/241596 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, SCV004822745.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (8)

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		6	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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