NM_000335.5(SCN5A):c.856G>T (p.Ala286Ser) AND not specified

Germline classification:: Likely benign (4 submissions)
Last evaluated:: Sep 17, 2018
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:: RCV000154846.17

Allele description [Variation Report for NM_000335.5(SCN5A):c.856G>T (p.Ala286Ser)]

NM_000335.5(SCN5A):c.856G>T (p.Ala286Ser)

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.856G>T (p.Ala286Ser)

Other names:

p.A286S:GCG>TCG

HGVS:

NC_000003.12:g.38609812C>A
NG_008934.1:g.44861G>T
NM_000335.5:c.856G>TMANE SELECT
NM_001099404.1:c.856G>T
NM_001099404.2:c.856G>T
NM_001099405.2:c.856G>T
NM_001160160.2:c.856G>T
NM_001160161.2:c.856G>T
NM_001354701.2:c.856G>T
NM_198056.3:c.856G>T
NP_000326.2:p.Ala286Ser
NP_001092874.1:p.Ala286Ser
NP_001092875.1:p.Ala286Ser
NP_001153632.1:p.Ala286Ser
NP_001153633.1:p.Ala286Ser
NP_001341630.1:p.Ala286Ser
NP_932173.1:p.Ala286Ser
NP_932173.1:p.Ala286Ser
LRG_289t1:c.856G>T
LRG_289t3:c.856G>T
LRG_289:g.44861G>T
LRG_289p1:p.Ala286Ser
NC_000003.11:g.38651303C>A
NM_198056.2:c.856G>T
Q14524:p.Ala286Ser

Protein change:

A286S

Links:

UniProtKB: Q14524#VAR_074339; dbSNP: rs61746118

NCBI 1000 Genomes Browser:

rs61746118

Molecular consequence:

NM_000335.5:c.856G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.856G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.856G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.856G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.856G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.856G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.856G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Homo sapiens retinol binding protein 5, cellular, mRNA (cDNA clone MGC:32522 IMAGE:4613026), complete cds
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000204528	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Apr 10, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19841300, 20129283, 24033266
SCV000235293	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (May 31, 2017)	germline	clinical testing	Citation Link,
SCV000918196	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Sep 17, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001926079	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
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

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000204528.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

proposed classification - variant undergoing re-assessment, contact laboratory

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From GeneDx, SCV000235293.6

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918196.1

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

Description

Variant summary: SCN5A c.856G>T (p.Ala286Ser) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 279948 control chromosomes, predominantly within the African subpopulation, at a frequency of 0.0029, in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 29-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.856G>T in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

#	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 Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001926079.1

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

#	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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