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NM_000335.5(SCN5A):c.934+4C>T AND not specified

Germline classification:
Likely benign (1 submission)
Last evaluated:
Jul 8, 2019
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001193951.9

Allele description [Variation Report for NM_000335.5(SCN5A):c.934+4C>T]

NM_000335.5(SCN5A):c.934+4C>T

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.934+4C>T
HGVS:
  • NC_000003.12:g.38609730G>A
  • NG_008934.1:g.44943C>T
  • NM_000335.5:c.934+4C>TMANE SELECT
  • NM_001099404.2:c.934+4C>T
  • NM_001099405.2:c.934+4C>T
  • NM_001160160.2:c.934+4C>T
  • NM_001160161.2:c.934+4C>T
  • NM_001354701.2:c.934+4C>T
  • NM_198056.3:c.934+4C>T
  • LRG_289t1:c.934+4C>T
  • LRG_289:g.44943C>T
  • NC_000003.11:g.38651221G>A
  • NM_198056.2:c.934+4C>T
Links:
dbSNP: rs182050752
NCBI 1000 Genomes Browser:
rs182050752
Molecular consequence:
  • NM_000335.5:c.934+4C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001099404.2:c.934+4C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001099405.2:c.934+4C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001160160.2:c.934+4C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001160161.2:c.934+4C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354701.2:c.934+4C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_198056.3:c.934+4C>T - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001363142Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Likely benign
(Jul 8, 2019) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing.

Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, Brugada P, Fressart V, Guerchicoff A, Harris-Kerr C, Kamakura S, Kyndt F, Koopmann TT, Miyamoto Y, Pfeiffer R, Pollevick GD, Probst V, Zumhagen S, Vatta M, Towbin JA, Shimizu W, Schulze-Bahr E, et al.

Heart Rhythm. 2010 Jan;7(1):33-46. doi: 10.1016/j.hrthm.2009.09.069. Epub 2009 Oct 8.

PubMed [citation]
PMID:
20129283
PMCID:
PMC2822446

The genetic component of Brugada syndrome.

Nielsen MW, Holst AG, Olesen SP, Olesen MS.

Front Physiol. 2013;4:179. doi: 10.3389/fphys.2013.00179.

PubMed [citation]
PMID:
23874304
PMCID:
PMC3710955
See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363142.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: SCN5A c.934+4C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00021 in 247310 control chromosomes, predominantly at a frequency of 0.00045 within the Non-Finnish European subpopulation in the gnomAD database. The variant allele was found within certain Non-Finnish European subpopulations at even higher frequencies, i.e. at a frequency of 0.00116 in the Swedish that is about 6.8 times higher than the expected maximum for a pathogenic variant in SCN5A causing Brugada Syndrome phenotype (0.00017), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Though the variant, c.934+4C>T, has been reported in the literature in an individual affected with Brugada Syndrome (Kapplinger_2010), it was also reported in a healthy individual (who had no ECG signs characteristic of Brugada syndrome) (Ghouse_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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

Last Updated: Oct 13, 2024