NM_000335.5(SCN5A):c.2977G>A (p.Ala993Thr) AND not provided

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 14, 2022
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:: RCV003654427.2

Allele description [Variation Report for NM_000335.5(SCN5A):c.2977G>A (p.Ala993Thr)]

NM_000335.5(SCN5A):c.2977G>A (p.Ala993Thr)

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.2977G>A (p.Ala993Thr)

HGVS:

NC_000003.12:g.38581182C>T
NG_008934.1:g.73491G>A
NG_053884.1:g.2921C>T
NM_000335.5:c.2977G>AMANE SELECT
NM_001099404.2:c.2977G>A
NM_001099405.2:c.2977G>A
NM_001160160.2:c.2977G>A
NM_001160161.2:c.2977G>A
NM_001354701.2:c.2977G>A
NM_198056.3:c.2977G>A
NP_000326.2:p.Ala993Thr
NP_001092874.1:p.Ala993Thr
NP_001092875.1:p.Ala993Thr
NP_001153632.1:p.Ala993Thr
NP_001153633.1:p.Ala993Thr
NP_001341630.1:p.Ala993Thr
NP_932173.1:p.Ala993Thr
NP_932173.1:p.Ala993Thr
LRG_289t1:c.2977G>A
LRG_289:g.73491G>A
LRG_289p1:p.Ala993Thr
NC_000003.11:g.38622673C>T
NM_198056.2:c.2977G>A
p.Ala993Thr

Protein change:

A993T

Links:

dbSNP: rs770088052

NCBI 1000 Genomes Browser:

rs770088052

Molecular consequence:

NM_000335.5:c.2977G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.2977G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.2977G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.2977G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.2977G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.2977G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.2977G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000637114	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 14, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27287068, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000637114

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 14, 2022)

germline

clinical testing

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Electrophysiological characterization of a large set of novel variants in the SCN5A-gene: identification of novel LQTS3 and BrS mutations.

Ortiz-Bonnin B, Rinné S, Moss R, Streit AK, Scharf M, Richter K, Stöber A, Pfeufer A, Seemann G, Kääb S, Beckmann BM, Decher N.

Pflugers Arch. 2016 Aug;468(8):1375-87. doi: 10.1007/s00424-016-1844-3. Epub 2016 Jun 11.

PubMed [citation]

PMID:: 27287068

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000637114.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 27287068). This variant is present in population databases (rs770088052, gnomAD 0.004%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 993 of the SCN5A protein (p.Ala993Thr). ClinVar contains an entry for this variant (Variation ID: 463317). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 27287068). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function.

#	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 24, 2024

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