Submissions for variant NM_198056.2(SCN5A):c.86_87invCA (p.Ala29Val)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001722268	SCV000235560	uncertain significance	not provided	2022-02-23	criteria provided, single submitter	clinical testing	A nucleotide substitution (c.86C>T) which results in the same amino acid substitution, A29V, has been reported in a patient with presyncope and a QTc of 490ms, who also harbored a pathogenic variant in the KCNQ1 gene (Stattin et al., 2012); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23098067, 33221895)
Invitae	RCV001722268	SCV000291838	uncertain significance	not provided	2024-01-20	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 (rs794728905, gnomAD 0.008%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 23098067, 28611029, 33221895). ClinVar contains an entry for this variant (Variation ID: 242209). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV000249341	SCV000320685	uncertain significance	Cardiovascular phenotype	2022-02-03	criteria provided, single submitter	clinical testing	The c.86_87delCAinsTG variant (also known as p.A29V), located in coding exon 1 of the SCN5A gene, results from an in-frame deletion of CA and insertion of TG at nucleotide positions 86 to 87. This results in the substitution of the alanine residue for a valine residue at codon 29, an amino acid with similar properties. This alteration has been reported in a Brugada syndrome cohort; however, clinical details were limited (Ciconte G et al. Eur Heart J, 2021 03;42:1082-1090). Another alteration at the same codon, p.A29V (c.86C>T), has been described in individuals with a prolonged QT interval and a sudden unexplained infant death cohort (Stattin EL et al. BMC Cardiovasc Disord, 2012 Oct;12:95; Methner DN et al. Genome Res, 2016 09;26:1170-7; Haskell GT et al. Circ Cardiovasc Genet, 2017 Jun;10:[ePub ahead of print]). Based on data from gnomAD, the TG allele has an overall frequency of 0.008% (22/280148) total alleles studied. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001843010	SCV001352603	uncertain significance	Cardiac arrhythmia	2022-10-11	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). A functional study has shown this variant reduces the sodium inward current (Murano et. al, 2019). This variant has been reported in an individual affected with Brugada syndrome (Murano et. al, 2019). 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.
Fulgent Genetics, Fulgent Genetics	RCV002500827	SCV002814907	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
PreventionGenetics, part of Exact Sciences	RCV003409361	SCV004112173	uncertain significance	SCN5A-related condition	2023-05-08	criteria provided, single submitter	clinical testing	The SCN5A c.86_87delinsTG variant is predicted to result in an in-frame deletion and insertion. This variant was reported in an individual with Brugada syndrome (Table S5, Ciconte et al. 2020. PubMed ID: 33221895). Of note, this variant may be reported in a large population database as two separate entries as c.87A>G (https://gnomad.broadinstitute.org/variant/3-38674712-T-C) and c.86C>T (https://gnomad.broadinstitute.org/variant/3-38674713-G-A). A similar variant resulting in the same amino acid substitution, c.86C>T (p.Ala29Val), has been reported in individuals with long QT syndrome, dilated cardiomyopathy, or sudden death (Stattin et al. 2012. PubMed ID: 23098067; Table S2, Methner et al. 2016. PubMed ID: 27435932; Table S2, Haskell et al. 2017. PubMed ID: 28611029). At this time, the clinical significance of the c.86_87delinsTG (p.Ala29Val) variant is uncertain due to the absence of conclusive functional and genetic evidence.