NM_000335.5(SCN5A):c.2923C>T (p.Arg975Trp) AND not provided

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Dec 19, 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:: RCV000058537.34

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000090057	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	no classification provided	not provided	germline	literature only	PubMed (5) [See all records that cite these PMIDs] 15851227, 19322600, 19841300, 20129283, 22581653
SCV000545022	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 19, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26669661, 32145446, 28492532
SCV001153869	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Nov 1, 2016)	germline	clinical testing	Citation Link,
SCV005198168	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 27, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only

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 (9)

Details of each submission

From Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, SCV000090057.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (5)

Description

This variant has been reported in the following publications (PMID:15851227;PMID:19322600;PMID:19841300;PMID:20129283).

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000545022.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 975 of the SCN5A protein (p.Arg975Trp). This variant is present in population databases (rs41311135, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of SCN5A-related conditions (PMID: 26669661, 32145446; Invitae). ClinVar contains an entry for this variant (Variation ID: 67767). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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 CeGaT Center for Human Genetics Tuebingen, SCV001153869.27

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

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

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005198168.1

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

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

Last Updated: Oct 26, 2024

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