chr3-38633221-TG-CA

Position:

• chr3-38633221-TG-CA

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The ENST00000423572.7(SCN5A):​c.86_87inv​(p.Ala29Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. A29A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 29)
• Consequence: SCN5A ENST00000423572.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 3.46

Genes affected

SCN5A (HGNC:10593): (sodium voltage-gated channel alpha subunit 5) The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 130) in uniprot entity SCN5A_HUMAN there are 24 pathogenic changes around while only 9 benign (73%) in ENST00000423572.7
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.8279 (greater than threshold 3.09). GenCC has associacion of gene with progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_000335.5	c.86_87inv	p.Ala29Val	missense_variant	2/28	ENST00000423572.7	NP_000326.2
SCN5A	NM_001099404.2	c.86_87inv	p.Ala29Val	missense_variant	2/28	ENST00000413689.6	NP_001092874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.86_87inv	p.Ala29Val	missense_variant	2/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.86_87inv	p.Ala29Val	missense_variant	2/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes Cov.: 29

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2022	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	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. -

SCN5A-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2023

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. -

SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 10, 2021

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

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. -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 11, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs794728905; hg19: chr3-38674712;