NM_000335.5(SCN5A):c.4214G>A (p.Gly1405Glu) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 27, 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:: RCV000183063.13

Allele description [Variation Report for NM_000335.5(SCN5A):c.4214G>A (p.Gly1405Glu)]

NM_000335.5(SCN5A):c.4214G>A (p.Gly1405Glu)

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.4214G>A (p.Gly1405Glu)

Other names:

p.G1406E:GGG>GAG

HGVS:

NC_000003.12:g.38560175C>T
NG_008934.1:g.94498G>A
NM_000335.5:c.4214G>AMANE SELECT
NM_001099404.2:c.4217G>A
NM_001099405.2:c.4217G>A
NM_001160160.2:c.4214G>A
NM_001160161.2:c.4055G>A
NM_001354701.2:c.4214G>A
NM_198056.3:c.4217G>A
NP_000326.2:p.Gly1405Glu
NP_001092874.1:p.Gly1406Glu
NP_001092875.1:p.Gly1406Glu
NP_001153632.1:p.Gly1405Glu
NP_001153633.1:p.Gly1352Glu
NP_001341630.1:p.Gly1405Glu
NP_932173.1:p.Gly1406Glu
NP_932173.1:p.Gly1406Glu
LRG_289t1:c.4217G>A
LRG_289:g.94498G>A
LRG_289p1:p.Gly1406Glu
NC_000003.11:g.38601666C>T
NM_198056.2:c.4217G>A
Q14524:p.Gly1406Glu

Protein change:

G1352E

Links:

UniProtKB: Q14524#VAR_074434; dbSNP: rs199473609

NCBI 1000 Genomes Browser:

rs199473609

Molecular consequence:

NM_000335.5:c.4214G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.4217G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.4217G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.4214G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.4055G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.4214G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.4217G>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
SCV000235472	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Sep 1, 2022)	germline	clinical testing	Citation Link,
SCV004292661	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 27, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20129283, 25904541, 32533946, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000235472

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Sep 1, 2022)

germline

clinical testing

Citation Link,

SCV004292661

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 27, 2023)

germline

clinical testing

PubMed (4)
[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	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

An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing.

Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, Brugada P, Fressart V, Guerchicoff A, Harris-Kerr C, Kamakura S, Kyndt F, Koopmann TT, Miyamoto Y, Pfeiffer R, Pollevick GD, Probst V, Zumhagen S, Vatta M, Towbin JA, Shimizu W, Schulze-Bahr E, et al.

Heart Rhythm. 2010 Jan;7(1):33-46. doi: 10.1016/j.hrthm.2009.09.069. Epub 2009 Oct 8.

PubMed [citation]

PMID:: 20129283
PMCID:: PMC2822446

Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A-Encoded Na(v)1.5 Cardiac Sodium Channel.

Kapplinger JD, Giudicessi JR, Ye D, Tester DJ, Callis TE, Valdivia CR, Makielski JC, Wilde AA, Ackerman MJ.

Circ Cardiovasc Genet. 2015 Aug;8(4):582-95. doi: 10.1161/CIRCGENETICS.114.000831. Epub 2015 Apr 22.

PubMed [citation]

PMID:: 25904541
PMCID:: PMC4878676

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000235472.12

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

Description

Identified in at least two individuals referred for genetic testing for Brugada syndrome (Kapplinger et al., 2010); however, no clinical information was provided; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies showed that p.(G1406E) resulted in a partial loss of peak current (Glazer et al., 2020); This variant is associated with the following publications: (PMID: 20129283, 30662450, 32569262, 31324802, 32533946)

#	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

From Invitae, SCV004292661.1

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

Description

Experimental studies have shown that this missense change affects SCN5A function (PMID: 32533946). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1406 of the SCN5A protein (p.Gly1406Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 20129283, 25904541, 32533946). ClinVar contains an entry for this variant (Variation ID: 67869). 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. 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

Last Updated: Jul 23, 2024

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