NM_000335.5(SCN5A):c.1813G>A (p.Gly605Arg) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 4, 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:: RCV003441970.3

Allele description [Variation Report for NM_000335.5(SCN5A):c.1813G>A (p.Gly605Arg)]

NM_000335.5(SCN5A):c.1813G>A (p.Gly605Arg)

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.1813G>A (p.Gly605Arg)

HGVS:

NC_000003.12:g.38603789C>T
NG_008934.1:g.50884G>A
NM_000335.5:c.1813G>AMANE SELECT
NM_001099404.2:c.1813G>A
NM_001099405.2:c.1813G>A
NM_001160160.2:c.1813G>A
NM_001160161.2:c.1813G>A
NM_001354701.2:c.1813G>A
NM_198056.3:c.1813G>A
NP_000326.2:p.Gly605Arg
NP_001092874.1:p.Gly605Arg
NP_001092875.1:p.Gly605Arg
NP_001153632.1:p.Gly605Arg
NP_001153633.1:p.Gly605Arg
NP_001341630.1:p.Gly605Arg
NP_932173.1:p.Gly605Arg
NP_932173.1:p.Gly605Arg
LRG_289t1:c.1813G>A
LRG_289:g.50884G>A
LRG_289p1:p.Gly605Arg
NC_000003.11:g.38645280C>T
NM_198056.2:c.1813G>A

Protein change:

G605R

Links:

dbSNP: rs1553704001

NCBI 1000 Genomes Browser:

rs1553704001

Molecular consequence:

NM_000335.5:c.1813G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.1813G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.1813G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.1813G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.1813G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.1813G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.1813G>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
SCV001546124	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 14, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004167840	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 4, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001546124

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 14, 2020)

germline

clinical testing

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

SCV004167840

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Apr 4, 2023)

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

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001546124.3

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

Description

This variant has not been reported in the literature in individuals with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 519522). This sequence change replaces glycine with arginine at codon 605 of the SCN5A protein (p.Gly605Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C65". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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, SCV004167840.1

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

Description

Has not been previously published as pathogenic or benign to our knowledge; 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

#	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: Nov 10, 2024

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