NM_000335.5(SCN5A):c.4744C>T (p.Arg1582Cys) AND Arrhythmia

Clinical significance:Uncertain significance (Last evaluated: Feb 25, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000850283.2

Allele description [Variation Report for NM_000335.5(SCN5A):c.4744C>T (p.Arg1582Cys)]

NM_000335.5(SCN5A):c.4744C>T (p.Arg1582Cys)

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.4744C>T (p.Arg1582Cys)
HGVS:
  • NC_000003.12:g.38554345G>A
  • NG_008934.1:g.100328C>T
  • NM_000335.5:c.4744C>TMANE SELECT
  • NM_001099404.2:c.4747C>T
  • NM_001099405.2:c.4693C>T
  • NM_001160160.2:c.4714+30C>T
  • NM_001160161.2:c.4585C>T
  • NM_001354701.2:c.4690C>T
  • NM_198056.2:c.4747C>T
  • NM_198056.3:c.4747C>T
  • NP_000326.2:p.Arg1582Cys
  • NP_001092874.1:p.Arg1583Cys
  • NP_001092875.1:p.Arg1565Cys
  • NP_001153633.1:p.Arg1529Cys
  • NP_001341630.1:p.Arg1564Cys
  • NP_932173.1:p.Arg1583Cys
  • NP_932173.1:p.Arg1583Cys
  • LRG_289t1:c.4747C>T
  • LRG_289:g.100328C>T
  • LRG_289p1:p.Arg1583Cys
  • NC_000003.11:g.38595836G>A
  • Q14524:p.Arg1583Cys
Protein change:
R1529C
Links:
UniProtKB: Q14524#VAR_074456; dbSNP: rs45514691
NCBI 1000 Genomes Browser:
rs45514691
Molecular consequence:
  • NM_001160160.2:c.4714+30C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000335.5:c.4744C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099404.2:c.4747C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099405.2:c.4693C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160161.2:c.4585C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354701.2:c.4690C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.2:c.4747C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.3:c.4747C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Arrhythmia
Identifiers:
EFO: EFO_0004269; MedGen: C0855329; Human Phenotype Ontology: HP:0011675

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000992458Institute of Human Genetics,University of Wuerzburgno assertion criteria providedLikely pathogenicunknownclinical testing

SCV001350456Color Health, Inccriteria provided, single submitter
Uncertain significance
(Feb 25, 2020)
germlineclinical testing

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

Description

This missense variant replaces arginine with cysteine at codon 1583 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals referred for Brugada syndrome genetic testing (PMID: 20129283, 24136861), in an individual affected with Brugada syndrome (PMID: 25650408), and in an individual affected with arrhythmia (Mizusawa et al., 2016). This variant has also been reported in an individual affected with sudden cardiac death, who also harbored a pathogenic splicing variant in the LMNA gene (Duong et al., 2017). This variant has been identified in 2/249188 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.

SCV001350456

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Institute of Human Genetics,University of Wuerzburg, SCV000992458.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Color Health, Inc, SCV001350456.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 20, 2021

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