NM_000335.5(SCN5A):c.2632C>T (p.Arg878Cys) AND Cardiovascular phenotype

Clinical significance:Likely pathogenic (Last evaluated: Aug 9, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000621112.1

Allele description [Variation Report for NM_000335.5(SCN5A):c.2632C>T (p.Arg878Cys)]

NM_000335.5(SCN5A):c.2632C>T (p.Arg878Cys)

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.2632C>T (p.Arg878Cys)
Other names:
p.R878C:CGC>TGC
HGVS:
  • NC_000003.12:g.38585846G>A
  • NG_008934.1:g.68827C>T
  • NM_000335.5:c.2632C>TMANE SELECT
  • NM_001099404.2:c.2632C>T
  • NM_001099405.2:c.2632C>T
  • NM_001160160.2:c.2632C>T
  • NM_001160161.2:c.2632C>T
  • NM_001354701.2:c.2632C>T
  • NM_198056.2:c.2632C>T
  • NM_198056.3:c.2632C>T
  • NP_000326.2:p.Arg878Cys
  • NP_001092874.1:p.Arg878Cys
  • NP_001092875.1:p.Arg878Cys
  • NP_001153632.1:p.Arg878Cys
  • NP_001153633.1:p.Arg878Cys
  • NP_001341630.1:p.Arg878Cys
  • NP_932173.1:p.Arg878Cys
  • NP_932173.1:p.Arg878Cys
  • LRG_289t1:c.2632C>T
  • LRG_289:g.68827C>T
  • LRG_289p1:p.Arg878Cys
  • NC_000003.11:g.38627337G>A
  • Q14524:p.Arg878Cys
Protein change:
R878C
Links:
UniProtKB: Q14524#VAR_055183; dbSNP: rs199473168
NCBI 1000 Genomes Browser:
rs199473168
Molecular consequence:
  • NM_000335.5:c.2632C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099404.2:c.2632C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099405.2:c.2632C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160160.2:c.2632C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160161.2:c.2632C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354701.2:c.2632C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.2:c.2632C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.3:c.2632C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000737852Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Aug 9, 2018)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Novel human pathological mutations.

[No authors listed]

Hum Genet. 2008 Jun;123(5):537-55. doi: 10.1007/s00439-008-0503-y. No abstract available.

PubMed [citation]
PMID:
18465145

Correlations between clinical and physiological consequences of the novel mutation R878C in a highly conserved pore residue in the cardiac Na+ channel.

Zhang Y, Wang T, Ma A, Zhou X, Gui J, Wan H, Shi R, Huang C, Grace AA, Huang CL, Trump D, Zhang H, Zimmer T, Lei M.

Acta Physiol (Oxf). 2008 Dec;194(4):311-23. doi: 10.1111/j.1748-1716.2008.01883.x. Epub 2008 Jul 24.

PubMed [citation]
PMID:
18616619
PMCID:
PMC2659387
See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV000737852.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (9)

Description

The p.R878C variant (also known as c.2632C>T), located in coding exon 15 of the SCN5A gene, results from a C to T substitution at nucleotide position 2632. The arginine at codon 878 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in individuals with Brugada syndrome and sick sinus syndrome (Savastano S et al. Heart Rhythm, 2014 Jul;11:1176-83; Crotti L et al., Hum. Genet., 2008 Jun;123:537-55; Crotti L et al. J. Am. Coll. Cardiol., 2012 Oct;60:1410-8; Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Zhang Y et al. Acta Physiol (Oxf), 2008 Dec;194:311-23). Segregation with disease has been reported in some families; however, clinical information was limited and some family members had additional variants (Crotti L et al., Hum. Genet., 2008 Jun;123:537-55; Zhang Y et al. Acta Physiol (Oxf), 2008 Dec;194:311-23; Bissay V et al. Eur. J. Hum. Genet., 2016 Mar;24:400-7; Van Malderen SCH et al. Circ. J., 2017 Dec;82:53-61).​ This variant is located in the S5-S6 pore-forming segment of the DII domain, and functional studies have demonstrated loss of sodium channel function despite proper localization in the cell membrane (Gui J et al. PLoS ONE, 2010 Jun;5:e10985; Zhang Y et al. Acta Physiol (Oxf), 2008 Dec;194:311-23). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Oct 30, 2021

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