NM_000335.5(SCN5A):c.3781G>A (p.Gly1261Ser) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 28, 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:: RCV001753410.5

Allele description [Variation Report for NM_000335.5(SCN5A):c.3781G>A (p.Gly1261Ser)]

NM_000335.5(SCN5A):c.3781G>A (p.Gly1261Ser)

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.3781G>A (p.Gly1261Ser)

HGVS:

NC_000003.12:g.38566465C>T
NG_008934.1:g.88208G>A
NM_000335.5:c.3781G>AMANE SELECT
NM_001099404.2:c.3784G>A
NM_001099405.2:c.3784G>A
NM_001160160.2:c.3781G>A
NM_001160161.2:c.3622G>A
NM_001354701.2:c.3781G>A
NM_198056.3:c.3784G>A
NP_000326.2:p.Gly1261Ser
NP_000326.2:p.Gly1261Ser
NP_001092874.1:p.Gly1262Ser
NP_001092875.1:p.Gly1262Ser
NP_001153632.1:p.Gly1261Ser
NP_001153633.1:p.Gly1208Ser
NP_001341630.1:p.Gly1261Ser
NP_932173.1:p.Gly1262Ser
NP_932173.1:p.Gly1262Ser
LRG_289t1:c.3784G>A
LRG_289t2:c.3781G>A
LRG_289:g.88208G>A
LRG_289p1:p.Gly1262Ser
LRG_289p2:p.Gly1261Ser
NC_000003.11:g.38607956C>T
NM_000335.4:c.3781G>A
NM_198056.2:c.3784G>A

Protein change:

G1208S; GLY1262SER

Links:

OMIM: 600163.0032; dbSNP: rs137854616

NCBI 1000 Genomes Browser:

rs137854616

Molecular consequence:

NM_000335.5:c.3781G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.3784G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.3784G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.3781G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.3622G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.3781G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.3784G>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
SCV000825694	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 28, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 32533946, 15338453, 20129283, 27554632, 30193851, 28492532
SCV001985375	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Nov 27, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000825694

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 28, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001985375

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Nov 27, 2019)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	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

Citations

PubMed

High-Throughput Reclassification of SCN5A Variants.

Glazer AM, Wada Y, Li B, Muhammad A, Kalash OR, O'Neill MJ, Shields T, Hall L, Short L, Blair MA, Kroncke BM, Capra JA, Roden DM.

Am J Hum Genet. 2020 Jul 2;107(1):111-123. doi: 10.1016/j.ajhg.2020.05.015. Epub 2020 Jun 12.

PubMed [citation]

PMID:: 32533946
PMCID:: PMC7332654

Genetic analysis of the cardiac sodium channel gene SCN5A in Koreans with Brugada syndrome.

Shin DJ, Jang Y, Park HY, Lee JE, Yang K, Kim E, Bae Y, Kim J, Kim J, Kim SS, Lee MH, Chahine M, Yoon SK.

J Hum Genet. 2004;49(10):573-578. doi: 10.1007/s10038-004-0182-z. Epub 2004 Aug 26.

PubMed [citation]

PMID:: 15338453

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000825694.3

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

Description

Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) indicates that this missense variant is expected to disrupt SCN5A function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32533946). 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. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1262 of the SCN5A protein (p.Gly1262Ser). This variant is present in population databases (rs137854616, gnomAD 0.01%). This missense change has been observed in individual(s) with Brugada syndrome and/or dilated cardiomyopathy or hypertrophic cardiomyopathy and Brugada syndrome (PMID: 15338453, 20129283, 27554632, 30193851). ClinVar contains an entry for this variant (Variation ID: 9399).

#	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 GeneDx, SCV001985375.2

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

Description

Reported in individuals with DCM and HCM (Priganc et al., 2016), an individual referred for Brugada syndrome testing (Kapplinger et al., 2010), and a child with noncompaction cardiomyopathy (van Waning et al., 2018); Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID#9399; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32048431, 31677787, 24903439, 19336922, 22581653, 18436145, 19027780, 15338453, 27554632, 29447731, 30662450, 20129283, 24136861, 31019283, 30193851, 31737537, 32533946, 33131149)

#	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: Sep 29, 2024

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