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NM_000335.5(SCN5A):c.3992C>T (p.Pro1331Leu) AND Long QT syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Aug 3, 2020
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:
RCV001255563.1

Allele description [Variation Report for NM_000335.5(SCN5A):c.3992C>T (p.Pro1331Leu)]

NM_000335.5(SCN5A):c.3992C>T (p.Pro1331Leu)

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.3992C>T (p.Pro1331Leu)
Other names:
p.P1332L:CCG>CTG
HGVS:
  • NC_000003.12:g.38560397G>A
  • NG_008934.1:g.94276C>T
  • NM_000335.5:c.3992C>TMANE SELECT
  • NM_001099404.2:c.3995C>T
  • NM_001099405.2:c.3995C>T
  • NM_001160160.2:c.3992C>T
  • NM_001160161.2:c.3833C>T
  • NM_001354701.2:c.3992C>T
  • NM_198056.3:c.3995C>T
  • NP_000326.2:p.Pro1331Leu
  • NP_001092874.1:p.Pro1332Leu
  • NP_001092875.1:p.Pro1332Leu
  • NP_001153632.1:p.Pro1331Leu
  • NP_001153633.1:p.Pro1278Leu
  • NP_001341630.1:p.Pro1331Leu
  • NP_932173.1:p.Pro1332Leu
  • NP_932173.1:p.Pro1332Leu
  • LRG_289t1:c.3995C>T
  • LRG_289:g.94276C>T
  • LRG_289p1:p.Pro1332Leu
  • NC_000003.11:g.38601888G>A
  • NM_198056.2:c.3995C>T
  • Q14524:p.Pro1332Leu
Protein change:
P1278L
Links:
UniProtKB: Q14524#VAR_055191; dbSNP: rs199473225
NCBI 1000 Genomes Browser:
rs199473225
Molecular consequence:
  • NM_000335.5:c.3992C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099404.2:c.3995C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099405.2:c.3995C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160160.2:c.3992C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160161.2:c.3833C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354701.2:c.3992C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.3:c.3995C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Long QT syndrome (LQTS)
Identifiers:
MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001432043Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Aug 3, 2020) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

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

Citations

PubMed

Genetic analysis, in silico prediction, and family segregation in long QT syndrome.

Riuró H, Campuzano O, Berne P, Arbelo E, Iglesias A, Pérez-Serra A, Coll-Vidal M, Partemi S, Mademont-Soler I, Picó F, Allegue C, Oliva A, Gerstenfeld E, Sarquella-Brugada G, Castro-Urda V, Fernández-Lozano I, Mont L, Brugada J, Scornik FS, Brugada R.

Eur J Hum Genet. 2015 Jan;23(1):79-85. doi: 10.1038/ejhg.2014.54. Epub 2014 Mar 26.

PubMed [citation]
PMID:
24667783
PMCID:
PMC4266740

Association of Genetic and Clinical Aspects of Congenital Long QT Syndrome With Life-Threatening Arrhythmias in Japanese Patients.

Shimizu W, Makimoto H, Yamagata K, Kamakura T, Wada M, Miyamoto K, Inoue-Yamada Y, Okamura H, Ishibashi K, Noda T, Nagase S, Miyazaki A, Sakaguchi H, Shiraishi I, Makiyama T, Ohno S, Itoh H, Watanabe H, Hayashi K, Yamagishi M, Morita H, Yoshinaga M, et al.

JAMA Cardiol. 2019 Mar 1;4(3):246-254. doi: 10.1001/jamacardio.2018.4925. Retraction in: JAMA Cardiol. 2021 Jun 1;6(6):727. doi: 10.1001/jamacardio.2021.1087.

PubMed [citation]
PMID:
30758498
PMCID:
PMC6439560
See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001432043.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: SCN5A c.3995C>T (p.Pro1332Leu) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251040 control chromosomes (gnomAD). c.3995C>T has been reported in the literature in multiple individuals affected with Long QT Syndrome and Brugada Syndrome (e.g. Ruan_2007, Riuro_2015, Liu_2018, Shimizu_2019). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated slower inactivation and prominent late Na+ currents (Ruan_2007, Liu_2018). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Sep 29, 2024