3-38579439-C-A

Position:

• chr3-38579439-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000335.5(SCN5A):​c.3282G>T​(p.Trp1094Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,460,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.08

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]

SCN5A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 267) in uniprot entity SCN5A_HUMAN there are 26 pathogenic changes around while only 11 benign (70%) in NM_000335.5
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.42118642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.3285G>T	p.Trp1095Cys	missense_variant	18/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3282G>T	p.Trp1094Cys	missense_variant	18/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.3285G>T	p.Trp1095Cys	missense_variant	18/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.3282G>T	p.Trp1094Cys	missense_variant	18/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000811 AC: 2 AN: 246604 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134458

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1460348 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726438

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2017	A variant of uncertain significance has been identified in the SCN5A gene. The W1095C variant has been published in one family with LQTS (Itoh et al., 2015); however, specific clinical details were not provided. Additionally, this substitution occurs at a position that is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Nevertheless, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The W1095C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2022	Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 29574140). 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. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 432236). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 26669661, 29574140). This variant is present in population databases (rs759924541, gnomAD 0.01%). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 1095 of the SCN5A protein (p.Trp1095Cys). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2020

The p.W1095C variant (also known as c.3285G>T), located in coding exon 17 of the SCN5A gene, results from a G to T substitution at nucleotide position 3285. The tryptophan at codon 1095 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was detected in two individuals from one family with long QT syndrome (LQTS) family; however, specific phenotypic information was not provided (Itoh H et al. Eur. J. Hum. Genet., 2016 08;24:1160-6). In addition, this alteration was detected once in a cohort of individuals with brugada syndrome who were symptomatic or had a family history of brugada syndrome, sudden death, syncope, or arrhythmic diseases (Sonoda K et al. Heart Rhythm, 2018 08;15:1179-1188). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
CardioboostCm	Benign	0.00091
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Uncertain	0.49	.;.;.;.;T;.
Eigen	Benign	0.076
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	.;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.42	T;T;T;T;T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.7	.;.;.;.;L;.
PROVEAN	Benign	-0.88	N;N;N;N;N;N
REVEL	Uncertain	0.61
Sift	Benign	0.17	T;T;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;T;T
Polyphen		0.65	P;P;.;P;P;P
Vest4		0.55
MutPred		0.44		Gain of loop (P = 0.0097);.;Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);.;
MVP		0.46
MPC		0.15
ClinPred		0.51	D
GERP RS		3.4
Varity_R		0.21
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs759924541; hg19: chr3-38620930;