NM_000335.5(SCN5A):c.103G>A (p.Gly35Ser) AND not specified

Germline classification:: Likely benign (1 submission)
Last evaluated:: Aug 8, 2022
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:: RCV002281902.8

Allele description [Variation Report for NM_000335.5(SCN5A):c.103G>A (p.Gly35Ser)]

NM_000335.5(SCN5A):c.103G>A (p.Gly35Ser)

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.103G>A (p.Gly35Ser)

HGVS:

NC_000003.12:g.38633205C>T
NG_008934.1:g.21468G>A
NM_000335.5:c.103G>AMANE SELECT
NM_001099404.2:c.103G>A
NM_001099405.2:c.103G>A
NM_001160160.2:c.103G>A
NM_001160161.2:c.103G>A
NM_001354701.2:c.103G>A
NM_198056.3:c.103G>A
NP_000326.2:p.Gly35Ser
NP_001092874.1:p.Gly35Ser
NP_001092875.1:p.Gly35Ser
NP_001153632.1:p.Gly35Ser
NP_001153633.1:p.Gly35Ser
NP_001341630.1:p.Gly35Ser
NP_932173.1:p.Gly35Ser
NP_932173.1:p.Gly35Ser
LRG_289t1:c.103G>A
LRG_289:g.21468G>A
LRG_289p1:p.Gly35Ser
NC_000003.11:g.38674696C>T
NM_198056.2:c.103G>A

Protein change:

G35S

Links:

dbSNP: rs199473552

NCBI 1000 Genomes Browser:

rs199473552

Molecular consequence:

NM_000335.5:c.103G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.103G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.103G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.103G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.103G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.103G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.103G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002571890	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Aug 8, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002571890

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Aug 8, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

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

Relationship between sodium channel function and clinical phenotype in SCN5A variants associated with Brugada syndrome.

Pearman CM, Denham NC, Mills RW, Ding WY, Modi SS, Hall MCS, Todd DM, Mahida S.

Hum Mutat. 2020 Dec;41(12):2195-2204. doi: 10.1002/humu.24128. Epub 2020 Nov 11.

PubMed [citation]

PMID:: 33131149
PMCID:: PMC7756571

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002571890.1

#	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.103G>A (p.Gly35Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.7e-05 in 248566 control chromosomes, predominantly at a frequency of 0.00018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.8 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 Non-Finnish European origin. To our knowledge, no penetrant association of c.103G>A in individuals affected with Brugada syndrome/Arrhythmia/SCN5A-related disorders have been reported. A recently published systematic literature review evaluating 561 SCN5A variants associated with Brugada syndrome reported this variant among a subset that were classified with an ACMG score of benign based on lack of impact on channel function (example, Pearman_2020). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=3). 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

Last Updated: Nov 10, 2024

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