NM_000335.5(SCN5A):c.3908C>T (p.Thr1303Met) AND Cardiovascular phenotype

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jan 4, 2024
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:
RCV000618218.13

Allele description [Variation Report for NM_000335.5(SCN5A):c.3908C>T (p.Thr1303Met)]

NM_000335.5(SCN5A):c.3908C>T (p.Thr1303Met)

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.3908C>T (p.Thr1303Met)
Other names:
p.T1304M:ACG>ATG
HGVS:
  • NC_000003.12:g.38562467G>A
  • NG_008934.1:g.92206C>T
  • NM_000335.5:c.3908C>TMANE SELECT
  • NM_001099404.2:c.3911C>T
  • NM_001099405.2:c.3911C>T
  • NM_001160160.2:c.3908C>T
  • NM_001160161.2:c.3749C>T
  • NM_001354701.2:c.3908C>T
  • NM_198056.3:c.3911C>T
  • NP_000326.2:p.Thr1303Met
  • NP_000326.2:p.Thr1303Met
  • NP_001092874.1:p.Thr1304Met
  • NP_001092874.1:p.Thr1304Met
  • NP_001092875.1:p.Thr1304Met
  • NP_001153632.1:p.Thr1303Met
  • NP_001153633.1:p.Thr1250Met
  • NP_001341630.1:p.Thr1303Met
  • NP_932173.1:p.Thr1304Met
  • NP_932173.1:p.Thr1304Met
  • LRG_289t1:c.3911C>T
  • LRG_289t2:c.3908C>T
  • LRG_289t3:c.3911C>T
  • LRG_289:g.92206C>T
  • LRG_289p1:p.Thr1304Met
  • LRG_289p2:p.Thr1303Met
  • LRG_289p3:p.Thr1304Met
  • NC_000003.11:g.38603958G>A
  • NM_000335.4:c.3908C>T
  • NM_001099404.1:c.3911C>T
  • NM_198056.2:c.3911C>T
Protein change:
T1250M
Links:
dbSNP: rs199473603
NCBI 1000 Genomes Browser:
rs199473603
Molecular consequence:
  • NM_000335.5:c.3908C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099404.2:c.3911C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099405.2:c.3911C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160160.2:c.3908C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160161.2:c.3749C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354701.2:c.3908C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.3:c.3911C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000736754Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Uncertain significance
(Jan 4, 2024) 		germlineclinical testing

PubMed (17)
[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

Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations.

Wattanasirichaigoon D, Vesely MR, Duggal P, Levine JC, Blume ED, Wolff GS, Edwards SB, Beggs AH.

Am J Med Genet. 1999 Oct 29;86(5):470-6.

PubMed [citation]
PMID:
10508990

Prevalence of long-QT syndrome gene variants in sudden infant death syndrome.

Arnestad M, Crotti L, Rognum TO, Insolia R, Pedrazzini M, Ferrandi C, Vege A, Wang DW, Rhodes TE, George AL Jr, Schwartz PJ.

Circulation. 2007 Jan 23;115(3):361-7. Epub 2007 Jan 8.

PubMed [citation]
PMID:
17210839
See all PubMed Citations (17)

Details of each submission

From Ambry Genetics, SCV000736754.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (17)

Description

The c.3911C>T (p.T1304M) alteration is located in exon 22 (coding exon 21) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 3911, causing the threonine (T) at amino acid position 1304 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of 0.017% (46/279030) total alleles studied. The highest observed frequency was 0.031% (40/127748) of European (non-Finnish) alleles. This alteration has been reported in association with long QT syndrome (Wattanasirichaigoon, 1999; Kapplinger, 2009). In one family, alteration carriers showed variable clinical and electrophysiological phenotypes with several having borderline findings (Wattanasirichaigoon, 1999). This alteration was also detected in individuals with a transient Brugada pattern, lone atrial fibrillation, or sudden infant death syndrome (Wang, 2007; Olesen, 2012; Wang, 2014; Kim, 2014). In addition, this alteration was reported in hypertrophic cardiomyopathy, dilated cardiomyopathy cohorts as well as exome sequencing and cohorts not selected for the presence of cardiovascular disease; however, limited clinical information was provided (Andreasen, 2013; Dorschner, 2013; Lopes, 2015; Amendola, 2015; Van Driest, 2016; Gigli, 2019; Diebold, 2020). This amino acid position is highly conserved in available vertebrate species. While some research groups reported that this alteration would lead to gain of function effects (Wang, 2007; Arnestad, 2007), others found no significant difference between mutant and wild type channel function (Makita, 2008; Beyder, 2014); however, the experimental systems were not the same and the physiological significance of these results is unclear. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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

Last Updated: Nov 10, 2024