Submissions for variant NM_000335.5(SCN5A):c.86C>T (p.Ala29Val)

gnomAD frequency: 0.00008  dbSNP: rs562675882

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182921	SCV000235316	uncertain significance	not provided	2017-11-30	criteria provided, single submitter	clinical testing	p.Ala29Val (GCA>GTG): c.86 C>T in exon 2 of the SCN5A gene (NM_198056.2) The Ala29Val variant in the SCN5A gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Although Ala29Val results in a conservative amino acid substitution of one non-polar residue for another, the Ala29 residue is conserved throughout evolution. In silico analysis predicts Ala29Val to be probably damaging to the structure/function of the protein and disease-causing. Mutations in nearby codons (Arg27His, Glu30Gly, Gly35Ser) have been reported in association with arrhythmia, supporting the functional importance of this region of the protein. The NHLBI ESP Exome Variant Server reports Ala29Val was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, with the clinical and molecular information available at this time, we cannot unequivocally determine if the Ala29Val variant in the SCN5A gene is a disease-causing mutation or a rare benign polymorphism. The variant is found in LQT panel(s).
CeGaT Center for Human Genetics Tuebingen	RCV000182921	SCV001153889	uncertain significance	not provided	2021-08-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001043149	SCV001206866	uncertain significance	Brugada syndrome	2022-07-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 29 of the SCN5A protein (p.Ala29Val). This variant is present in population databases (rs562675882, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with KCNQ1-related conditions (PMID: 23098067, 28611029, 33221895). ClinVar contains an entry for this variant (Variation ID: 201428). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002500541	SCV002776559	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2021-11-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996807	SCV004833643	uncertain significance	Cardiac arrhythmia	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 29 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with long QT syndrome, who also carried a pathogenic variant in the KCNQ1 gene that could explain the observed phenotype (PMID: 23098067). This variant has also been reported in another individual with dilated cardiomyopathy and long QT phenotypes (PMID: 28611029). This variant has been identified in 27/280148 chromosomes 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV004546451	SCV005042911	uncertain significance	Brugada syndrome 1		criteria provided, single submitter	clinical testing	The missense c.86C>T p.Ala29Val variant in SCN5A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ala29Val variant is reported with an allele frequency of 0.008% in the gnomAD exomes database. This variant has been reported to the ClinVar database as Uncertain Significance multiple submissions. The amino acid change p.Ala29Val in SCN5A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 29 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance VUS.