NM_000335.5(SCN5A):c.3997A>G (p.Ile1333Val) AND Brugada syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 24, 2016
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:: RCV000456774.1

Allele description [Variation Report for NM_000335.5(SCN5A):c.3997A>G (p.Ile1333Val)]

NM_000335.5(SCN5A):c.3997A>G (p.Ile1333Val)

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.3997A>G (p.Ile1333Val)

Other names:

p.I1334V:ATC>GTC

HGVS:

NC_000003.12:g.38560392T>C
NG_008934.1:g.94281A>G
NM_000335.5:c.3997A>GMANE SELECT
NM_001099404.2:c.4000A>G
NM_001099405.2:c.4000A>G
NM_001160160.2:c.3997A>G
NM_001160161.2:c.3838A>G
NM_001354701.2:c.3997A>G
NM_198056.3:c.4000A>G
NP_000326.2:p.Ile1333Val
NP_001092874.1:p.Ile1334Val
NP_001092875.1:p.Ile1334Val
NP_001153632.1:p.Ile1333Val
NP_001153633.1:p.Ile1280Val
NP_001341630.1:p.Ile1333Val
NP_932173.1:p.Ile1334Val
NP_932173.1:p.Ile1334Val
LRG_289t1:c.4000A>G
LRG_289:g.94281A>G
LRG_289p1:p.Ile1334Val
NC_000003.11:g.38601883T>C
NM_198056.2:c.4000A>G
Q14524:p.Ile1334Val

Protein change:

I1280V

Links:

UniProtKB: Q14524#VAR_074736; dbSNP: rs199473226

NCBI 1000 Genomes Browser:

rs199473226

Molecular consequence:

NM_000335.5:c.3997A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.4000A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.4000A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.3997A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.3838A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.3997A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.4000A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Brugada syndrome
Synonyms:: Sudden unexpected nocturnal death syndrome; Sudden unexplained nocturnal death syndrome; Sudden Unexplained Death Syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015263; MedGen: C1142166; OMIM: PS601144

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000545050	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 24, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000545050

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 24, 2016)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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 Invitae, SCV000545050.2

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

Description

This sequence change replaces isoleucine with valine at codon 1334 of the SCN5A protein (p.Ile1334Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs199473226, ExAC 0.002%). This variant was reported in individuals referred for long QT testing (PMID: 19716085, 23098067). ClinVar contains an entry for this variant (Variation ID: 67847). This variant identified in the SCN5A gene is located in the transmembrane spanning DIII-S4/S5 region of the resulting protein (PMID: 25348405), but it is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the general population and individuals referred for longQT testing, but the available evidence is currently insufficient to determine its role 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

Last Updated: May 1, 2024

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