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NM_000335.5(SCN5A):c.3890C>T (p.Pro1297Leu) AND Cardiac arrhythmia

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Dec 10, 2018
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:
RCV001841240.10

Allele description [Variation Report for NM_000335.5(SCN5A):c.3890C>T (p.Pro1297Leu)]

NM_000335.5(SCN5A):c.3890C>T (p.Pro1297Leu)

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.3890C>T (p.Pro1297Leu)
HGVS:
  • NC_000003.12:g.38562485G>A
  • NG_008934.1:g.92188C>T
  • NM_000335.5:c.3890C>TMANE SELECT
  • NM_001099404.2:c.3893C>T
  • NM_001099405.2:c.3893C>T
  • NM_001160160.2:c.3890C>T
  • NM_001160161.2:c.3731C>T
  • NM_001354701.2:c.3890C>T
  • NM_198056.3:c.3893C>T
  • NP_000326.2:p.Pro1297Leu
  • NP_001092874.1:p.Pro1298Leu
  • NP_001092875.1:p.Pro1298Leu
  • NP_001153632.1:p.Pro1297Leu
  • NP_001153633.1:p.Pro1244Leu
  • NP_001341630.1:p.Pro1297Leu
  • NP_932173.1:p.Pro1298Leu
  • NP_932173.1:p.Pro1298Leu
  • LRG_289t1:c.3893C>T
  • LRG_289:g.92188C>T
  • LRG_289p1:p.Pro1298Leu
  • NC_000003.11:g.38603976G>A
  • NM_198056.2:c.3893C>T
Protein change:
P1244L; PRO1298LEU
Links:
OMIM: 600163.0025; dbSNP: rs28937319
NCBI 1000 Genomes Browser:
rs28937319
Molecular consequence:
  • NM_000335.5:c.3890C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099404.2:c.3893C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099405.2:c.3893C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160160.2:c.3890C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160161.2:c.3731C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354701.2:c.3890C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.3:c.3893C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001350252Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Dec 10, 2018) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001350252.2

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

Description

Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the transmembrane domain DIII of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental studies have shown that this variant may alter sodium channel kinetics (PMID: 20384651, 20448214, 20539757). However, clinical significance of these observations is not clear. This variant has been reported in compound heterozygosity with a pathogenic p.Gly1408Arg variant in three siblings affected with congenital sick sinus syndrome (PMID: 14523039). Eleven heterozygous carriers of this variant were asymptomatic and largely without electrocardiographic abnormalities, except the proband's maternal grandmother, who had first-degree heart block. In this family, heterozygous p.Gly1408Arg variant segregated with first-degree heart block phenotype in multiple individuals. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the pathogenicity of this variant conclusively. Medical management should be considered based on personal and family history.

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

Last Updated: Nov 3, 2024