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NM_000335.5(SCN5A):c.2077C>T (p.Arg693Cys) AND Cardiac arrhythmia

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Dec 1, 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:
RCV001841399.13

Allele description [Variation Report for NM_000335.5(SCN5A):c.2077C>T (p.Arg693Cys)]

NM_000335.5(SCN5A):c.2077C>T (p.Arg693Cys)

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.2077C>T (p.Arg693Cys)
HGVS:
  • NC_000003.12:g.38597914G>A
  • NG_008934.1:g.56759C>T
  • NM_000335.5:c.2077C>TMANE SELECT
  • NM_001099404.2:c.2077C>T
  • NM_001099405.2:c.2077C>T
  • NM_001160160.2:c.2077C>T
  • NM_001160161.2:c.2077C>T
  • NM_001354701.2:c.2077C>T
  • NM_198056.3:c.2077C>T
  • NP_000326.2:p.Arg693Cys
  • NP_001092874.1:p.Arg693Cys
  • NP_001092875.1:p.Arg693Cys
  • NP_001153632.1:p.Arg693Cys
  • NP_001153633.1:p.Arg693Cys
  • NP_001341630.1:p.Arg693Cys
  • NP_932173.1:p.Arg693Cys
  • NP_932173.1:p.Arg693Cys
  • LRG_289t1:c.2077C>T
  • LRG_289:g.56759C>T
  • LRG_289p1:p.Arg693Cys
  • NC_000003.11:g.38639405G>A
  • NM_001099404.1:c.2077C>T
  • NM_198056.2:c.2077C>T
Protein change:
R693C
Links:
dbSNP: rs375306544
NCBI 1000 Genomes Browser:
rs375306544
Molecular consequence:
  • NM_000335.5:c.2077C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099404.2:c.2077C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099405.2:c.2077C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160160.2:c.2077C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160161.2:c.2077C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354701.2:c.2077C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.3:c.2077C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
14

Condition(s)

Name:
Cardiac arrhythmia
Synonyms:
Cardiac rhythm disease
Identifiers:
EFO: EFO_0004269; MONDO: MONDO:0007263; MedGen: C0003811; Human Phenotype Ontology: HP:0011675

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001351114Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Nov 16, 2022) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004817103All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Dec 1, 2023) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown14not providednot provided108544not providedclinical testing

Citations

PubMed

Genotype-Phenotype Correlation of SCN5A Mutation for the Clinical and Electrocardiographic Characteristics of Probands With Brugada Syndrome: A Japanese Multicenter Registry.

Yamagata K, Horie M, Aiba T, Ogawa S, Aizawa Y, Ohe T, Yamagishi M, Makita N, Sakurada H, Tanaka T, Shimizu A, Hagiwara N, Kishi R, Nakano Y, Takagi M, Makiyama T, Ohno S, Fukuda K, Watanabe H, Morita H, Hayashi K, Kusano K, et al.

Circulation. 2017 Jun 6;135(23):2255-2270. doi: 10.1161/CIRCULATIONAHA.117.027983. Epub 2017 Mar 24.

PubMed [citation]
PMID:
28341781

Role of extensive diagnostic workup in young athletes and nonathletes with complex ventricular arrhythmias.

Narducci ML, Pelargonio G, La Rosa G, Inzani F, d'Amati G, Novelli V, Marano R, Perna F, Bencardino G, Pinnacchio G, Genuardi M, Cammarano M, Palmieri V, Zeppilli P, Crea F.

Heart Rhythm. 2020 Feb;17(2):230-237. doi: 10.1016/j.hrthm.2019.08.022. Epub 2019 Aug 28.

PubMed [citation]
PMID:
31470130
See all PubMed Citations (3)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001351114.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This missense variant replaces arginine with cysteine at codon 693 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with aborted cardiac arrest (PMID: 28341781) and in an individual affected with complex ventricular arrhythmia (PMID: 31470130). This variant has been identified in 13/249020 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004817103.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided14not providednot providedclinical testing PubMed (3)

Description

This missense variant replaces arginine with cysteine at codon 693 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with aborted cardiac arrest (PMID: 28341781) and in an individual affected with complex ventricular arrhythmia (PMID: 31470130). This variant has been identified in 13/249020 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided14not providednot providednot provided

Last Updated: Oct 13, 2024