NM_000335.5(SCN5A):c.1705C>G (p.Arg569Gly) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 7, 2022
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:: RCV000183172.14

Allele description [Variation Report for NM_000335.5(SCN5A):c.1705C>G (p.Arg569Gly)]

NM_000335.5(SCN5A):c.1705C>G (p.Arg569Gly)

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.1705C>G (p.Arg569Gly)

Other names:

p.R569G:CGG>GGG

HGVS:

NC_000003.12:g.38603897G>C
NG_008934.1:g.50776C>G
NM_000335.5:c.1705C>GMANE SELECT
NM_001099404.2:c.1705C>G
NM_001099405.2:c.1705C>G
NM_001160160.2:c.1705C>G
NM_001160161.2:c.1705C>G
NM_001354701.2:c.1705C>G
NM_198056.3:c.1705C>G
NP_000326.2:p.Arg569Gly
NP_001092874.1:p.Arg569Gly
NP_001092875.1:p.Arg569Gly
NP_001092875.1:p.Arg569Gly
NP_001153632.1:p.Arg569Gly
NP_001153633.1:p.Arg569Gly
NP_001341630.1:p.Arg569Gly
NP_932173.1:p.Arg569Gly
NP_932173.1:p.Arg569Gly
LRG_289t1:c.1705C>G
LRG_289:g.50776C>G
LRG_289p1:p.Arg569Gly
NC_000003.11:g.38645388G>C
NM_001099405.1:c.1705C>G
NM_198056.2:c.1705C>G

Protein change:

R569G

Links:

dbSNP: rs199473576

NCBI 1000 Genomes Browser:

rs199473576

Molecular consequence:

NM_000335.5:c.1705C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.1705C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.1705C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.1705C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.1705C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.1705C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.1705C>G - 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
SCV000235589	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Sep 7, 2022)	germline	clinical testing	Citation Link,
SCV002969291	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 20, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 30662450, 32233023, 25904541, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000235589

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Sep 7, 2022)

germline

clinical testing

Citation Link,

SCV002969291

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 20, 2022)

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

Impact of Ancestral Differences and Reassessment of the Classification of Previously Reported Pathogenic Variants in Patients With Brugada Syndrome in the Genomic Era: A SADS-TW BrS Registry.

Chen CJ, Lu TP, Lin LY, Liu YB, Ho LT, Huang HC, Lai LP, Hwang JJ, Yeh SS, Wu CK, Juang JJ, Antzelevitch C.

Front Genet. 2018;9:680. doi: 10.3389/fgene.2018.00680.

PubMed [citation]

PMID:: 30662450
PMCID:: PMC6328444

Wolff-Parkinson-White syndrome: De novo variants and evidence for mutational burden in genes associated with atrial fibrillation.

Coban-Akdemir ZH, Charng WL, Azamian M, Paine IS, Punetha J, Grochowski CM, Gambin T, Valdes SO, Cannon B, Zapata G, Hernandez PP, Jhangiani S, Doddapaneni H, Hu J, Boricha F, Muzny DM, Boerwinkle E, Yang Y, Gibbs RA, Posey JE, Wehrens XHT, Belmont JW, et al.

Am J Med Genet A. 2020 Jun;182(6):1387-1399. doi: 10.1002/ajmg.a.61571. Epub 2020 Mar 31.

PubMed [citation]

PMID:: 32233023
PMCID:: PMC7275694

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000235589.12

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

Description

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; This variant is associated with the following publications: (PMID: 32233023, 30662450, 25904541)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002969291.2

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

Description

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 569 of the SCN5A protein (p.Arg569Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 30662450, 32233023). ClinVar contains an entry for this variant (Variation ID: 201576). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). Experimental studies have shown that this missense change affects SCN5A function (PMID: 25904541). 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: Oct 8, 2024

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