NM_000335.5(SCN5A):c.2182G>A (p.Val728Ile) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 17, 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:: RCV001759475.11

Allele description [Variation Report for NM_000335.5(SCN5A):c.2182G>A (p.Val728Ile)]

NM_000335.5(SCN5A):c.2182G>A (p.Val728Ile)

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.2182G>A (p.Val728Ile)

HGVS:

NC_000003.12:g.38597809C>T
NG_008934.1:g.56864G>A
NM_000335.5:c.2182G>AMANE SELECT
NM_001099404.2:c.2182G>A
NM_001099405.2:c.2182G>A
NM_001160160.2:c.2182G>A
NM_001160161.2:c.2182G>A
NM_001354701.2:c.2182G>A
NM_198056.3:c.2182G>A
NP_000326.2:p.Val728Ile
NP_000326.2:p.Val728Ile
NP_001092874.1:p.Val728Ile
NP_001092875.1:p.Val728Ile
NP_001153632.1:p.Val728Ile
NP_001153633.1:p.Val728Ile
NP_001341630.1:p.Val728Ile
NP_932173.1:p.Val728Ile
NP_932173.1:p.Val728Ile
LRG_289t1:c.2182G>A
LRG_289t2:c.2182G>A
LRG_289:g.56864G>A
LRG_289p1:p.Val728Ile
LRG_289p2:p.Val728Ile
NC_000003.11:g.38639300C>T
NM_000335.4:c.2182G>A
NM_198056.2:c.2182G>A

Protein change:

V728I

Links:

dbSNP: rs958480279

NCBI 1000 Genomes Browser:

rs958480279

Molecular consequence:

NM_000335.5:c.2182G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.2182G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.2182G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.2182G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.2182G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.2182G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.2182G>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
SCV001556999	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 17, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 14985827, 22984773, 33221895, 28492532
SCV001987407	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Oct 14, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001556999

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 17, 2023)

germline

clinical testing

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

SCV001987407

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Oct 14, 2021)

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

[Single nucleotide polymorphism in SCN5A and the distribution in Chinese Han ethnic group].

Xie XD, Wang XX, Chen JZ, Tao M, Shang YP, Guo XG, Zheng LR.

Sheng Li Xue Bao. 2004 Feb 25;56(1):36-40. Chinese.

PubMed [citation]

PMID:: 14985827

A study of the SCN5A gene in a cohort of 76 patients with Brugada syndrome.

García-Molina E, Lacunza J, Ruiz-Espejo F, Sabater M, García-Alberola A, Gimeno JR, Cañizares F, García A, Martínez P, Valdés M, Tovar I.

Clin Genet. 2013 Jun;83(6):530-8. doi: 10.1111/cge.12017. Epub 2012 Oct 16.

PubMed [citation]

PMID:: 22984773

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001556999.3

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

Description

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 728 of the SCN5A protein (p.Val728Ile). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with Brugada syndrome and/or SCN5A-related conditions (PMID: 14985827, 22984773, 33221895). ClinVar contains an entry for this variant (Variation ID: 633412). 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 tolerated. 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 GeneDx, SCV001987407.2

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

Description

Reported in a cohort of individuals with Brugada syndrome, however, patient-specific data were not provided (Ciconte et al., 2021); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 633412; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30662450, 26582918, 22984773, 33221895)

#	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: May 1, 2024

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