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NM_000335.5(SCN5A):c.4027T>C (p.Phe1343Leu) AND Cardiac arrhythmia

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Dec 18, 2023
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:
RCV003996539.2

Allele description [Variation Report for NM_000335.5(SCN5A):c.4027T>C (p.Phe1343Leu)]

NM_000335.5(SCN5A):c.4027T>C (p.Phe1343Leu)

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.4027T>C (p.Phe1343Leu)
HGVS:
  • NC_000003.12:g.38560362A>G
  • NG_008934.1:g.94311T>C
  • NM_000335.5:c.4027T>CMANE SELECT
  • NM_001099404.2:c.4030T>C
  • NM_001099405.2:c.4030T>C
  • NM_001160160.2:c.4027T>C
  • NM_001160161.2:c.3868T>C
  • NM_001354701.2:c.4027T>C
  • NM_198056.3:c.4030T>C
  • NP_000326.2:p.Phe1343Leu
  • NP_001092874.1:p.Phe1344Leu
  • NP_001092875.1:p.Phe1344Leu
  • NP_001153632.1:p.Phe1343Leu
  • NP_001153633.1:p.Phe1290Leu
  • NP_001341630.1:p.Phe1343Leu
  • NP_932173.1:p.Phe1344Leu
  • NP_932173.1:p.Phe1344Leu
  • LRG_289t1:c.4030T>C
  • LRG_289:g.94311T>C
  • LRG_289p1:p.Phe1344Leu
  • NC_000003.11:g.38601853A>G
  • NM_198056.2:c.4030T>C
Protein change:
F1290L
Links:
dbSNP: rs199473228
NCBI 1000 Genomes Browser:
rs199473228
Molecular consequence:
  • NM_000335.5:c.4027T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099404.2:c.4030T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099405.2:c.4030T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160160.2:c.4027T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160161.2:c.3868T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354701.2:c.4027T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.3:c.4030T>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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
SCV004840874All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Dec 18, 2023) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided108544not 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

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Walsh R, Lahrouchi N, Tadros R, Kyndt F, Glinge C, Postema PG, Amin AS, Nannenberg EA, Ware JS, Whiffin N, Mazzarotto F, Škorić-Milosavljević D, Krijger C, Arbelo E, Babuty D, Barajas-Martinez H, Beckmann BM, Bézieau S, Bos JM, Breckpot J, Campuzano O, Castelletti S, et al.

Genet Med. 2021 Jan;23(1):47-58. doi: 10.1038/s41436-020-00946-5. Epub 2020 Sep 7.

PubMed [citation]
PMID:
32893267
PMCID:
PMC7790744
See all PubMed Citations (3)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004840874.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)

Description

This missense variant replaces phenylalanine with leucine at codon 1344 of the SCN5A protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved transmembrane domain (a.a. 1207-1466). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Brugada syndrome (PMID: 20129283, 32893267). This variant has not been identified 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 provided1not providednot providednot provided

Last Updated: Sep 29, 2024