NM_000335.5(SCN5A):c.3337G>A (p.Asp1113Asn) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 20, 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:: RCV001572250.13

Allele description [Variation Report for NM_000335.5(SCN5A):c.3337G>A (p.Asp1113Asn)]

NM_000335.5(SCN5A):c.3337G>A (p.Asp1113Asn)

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.3337G>A (p.Asp1113Asn)

HGVS:

NC_000003.12:g.38579384C>T
NG_008934.1:g.75289G>A
NG_053884.1:g.1123C>T
NM_000335.5:c.3337G>AMANE SELECT
NM_001099404.2:c.3340G>A
NM_001099405.2:c.3340G>A
NM_001160160.2:c.3337G>A
NM_001160161.2:c.3228+1547G>A
NM_001354701.2:c.3337G>A
NM_198056.3:c.3340G>A
NP_000326.2:p.Asp1113Asn
NP_001092874.1:p.Asp1114Asn
NP_001092875.1:p.Asp1114Asn
NP_001153632.1:p.Asp1113Asn
NP_001341630.1:p.Asp1113Asn
NP_932173.1:p.Asp1114Asn
NP_932173.1:p.Asp1114Asn
LRG_289t1:c.3340G>A
LRG_289:g.75289G>A
LRG_289p1:p.Asp1114Asn
NC_000003.11:g.38620875C>T
NM_198056.2:c.3340G>A

Protein change:

D1113N

Links:

dbSNP: rs199473195

NCBI 1000 Genomes Browser:

rs199473195

Molecular consequence:

NM_001160161.2:c.3228+1547G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000335.5:c.3337G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.3340G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.3340G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.3337G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.3337G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.3340G>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
SCV000956717	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 20, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10973849, 11076825, 25904541, 28492532
SCV001796858	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 18, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000956717

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 20, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001796858

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Apr 18, 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

Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.

Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT.

Circulation. 2000 Sep 5;102(10):1178-85.

PubMed [citation]

PMID:: 10973849

Clinical and genetic heterogeneity of right bundle branch block and ST-segment elevation syndrome: A prospective evaluation of 52 families.

Priori SG, Napolitano C, Gasparini M, Pappone C, Della Bella P, Brignole M, Giordano U, Giovannini T, Menozzi C, Bloise R, Crotti L, Terreni L, Schwartz PJ.

Circulation. 2000 Nov 14;102(20):2509-15.

PubMed [citation]

PMID:: 11076825

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000956717.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This missense change has been observed in individuals with clinical features of long QT syndrome and Brugada syndrome (PMID: 10973849, 11076825, 25904541). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 67792). This variant is present in population databases (rs199473195, gnomAD 0.004%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1114 of the SCN5A protein (p.Asp1114Asn).

#	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, SCV001796858.1

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

Description

Reported in association with arrhythmias (Splawski et al., 2000; Kapplinger et al., 2009); Identified in one individual with sudden cardiac death and was also present in nine asymptomatic family members (Priori et a., 2000); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19716085, 10973849, 15047701, 19336922, 19027780, 18436145, 24599044, 16540748, 12188452, 14753626, 14961552, 11076825, 9612375)

#	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 13, 2024

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