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NM_000335.5(SCN5A):c.1595T>G (p.Phe532Cys) AND Cardiac arrhythmia

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jan 11, 2024
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:
RCV001842287.13

Allele description

NM_000335.5(SCN5A):c.1595T>G (p.Phe532Cys)

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.1595T>G (p.Phe532Cys)
Other names:
p.F532C:TTT>TGT
HGVS:
  • NC_000003.12:g.38604007A>C
  • NG_008934.1:g.50666T>G
  • NM_000335.5:c.1595T>GMANE SELECT
  • NM_001099404.2:c.1595T>G
  • NM_001099405.2:c.1595T>G
  • NM_001160160.2:c.1595T>G
  • NM_001160161.2:c.1595T>G
  • NM_001354701.2:c.1595T>G
  • NM_198056.3:c.1595T>G
  • NP_000326.2:p.Phe532Cys
  • NP_001092874.1:p.Phe532Cys
  • NP_001092875.1:p.Phe532Cys
  • NP_001153632.1:p.Phe532Cys
  • NP_001153633.1:p.Phe532Cys
  • NP_001341630.1:p.Phe532Cys
  • NP_932173.1:p.Phe532Cys
  • NP_932173.1:p.Phe532Cys
  • LRG_289t1:c.1595T>G
  • LRG_289:g.50666T>G
  • LRG_289p1:p.Phe532Cys
  • NC_000003.11:g.38645498A>C
  • NM_198056.2:c.1595T>G
  • Q14524:p.Phe532Cys
Protein change:
F532C
Links:
UniProtKB: Q14524#VAR_055177; dbSNP: rs199473573
NCBI 1000 Genomes Browser:
rs199473573
Molecular consequence:
  • NM_000335.5:c.1595T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099404.2:c.1595T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099405.2:c.1595T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160160.2:c.1595T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160161.2:c.1595T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354701.2:c.1595T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.3:c.1595T>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
3

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
SCV001342757Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Jul 13, 2023) 		germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV004839433All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Jan 11, 2024) 		germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown3not providednot provided108544not providedclinical testing

Citations

PubMed

Genetic polymorphisms and haplotypes of the human cardiac sodium channel alpha subunit gene (SCN5A) in Japanese and their association with arrhythmia.

Maekawa K, Saito Y, Ozawa S, Adachi-Akahane S, Kawamoto M, Komamura K, Shimizu W, Ueno K, Kamakura S, Kamatani N, Kitakaze M, Sawada J.

Ann Hum Genet. 2005 Jul;69(Pt 4):413-28.

PubMed [citation]
PMID:
15996170

Cardiac ion channel gene mutations in sudden infant death syndrome.

Otagiri T, Kijima K, Osawa M, Ishii K, Makita N, Matoba R, Umetsu K, Hayasaka K.

Pediatr Res. 2008 Nov;64(5):482-7. doi: 10.1203/PDR.0b013e3181841eca.

PubMed [citation]
PMID:
18596570
See all PubMed Citations (9)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001342757.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This missense variant replaces phenylalanine with cysteine at codon 532 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). Functional studies have shown that this variant causes a reduction of sodium current density in transfected rat neonatal cardiomyocytes but no changes in channel function found in transfected human kidney cell line tsA-201 (PMID: 18596570, 34843967). This variant has been reported in three individuals affected with or suspected of having Brugada syndrome (PMID: 20129283, 28341781, 32893267), and in other individuals affected with arrhythmia (PMID: 15996170), sudden infant death syndrome (PMID: 18596570), or sudden unexpected death (PMID: 32449611). This variant has also been reported in 2 related individuals with normal electrocardiograms exhibiting no type 1 Brugada ECG pattern or any T-wave abnormalities (PMID: 29062695). This variant has been identified in 4/247568 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, SCV004839433.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testing PubMed (9)

Description

This missense variant replaces phenylalanine with cysteine at codon 532 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). Functional studies have shown that this variant causes a reduction of sodium current density in transfected rat neonatal cardiomyocytes but no changes in channel function found in transfected human kidney cell line tsA-201 (PMID: 18596570, 34843967). This variant has been reported in three individuals affected with or suspected of having Brugada syndrome (PMID: 20129283, 28341781, 32893267), and in other individuals affected with arrhythmia (PMID: 15996170), sudden infant death syndrome (PMID: 18596570), or sudden unexpected death (PMID: 32449611). This variant has also been reported in 2 related individuals with normal electrocardiograms exhibiting no type 1 Brugada ECG pattern or any T-wave abnormalities (PMID: 29062695). This variant has been identified in 4/247568 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 provided3not providednot providednot provided

Last Updated: Feb 25, 2025