3-38579474-C-T

Position:

• chr3-38579474-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_000335.5(SCN5A):​c.3247G>A​(p.Gly1083Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,459,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: -0.520

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 3 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=0.13329089).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.3250G>A	p.Gly1084Ser	missense_variant	18/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3247G>A	p.Gly1083Ser	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.3250G>A	p.Gly1084Ser	missense_variant	18/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.3247G>A	p.Gly1083Ser	missense_variant	18/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000818 AC: 2 AN: 244388 Hom.: 0 AF XY: 0.00000748 AC XY: 1 AN XY: 133606

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: 0.0000164 AC: 24 AN: 1459260 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 725820

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000330 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Aug 20, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1084 of the SCN5A protein (p.Gly1084Ser). This variant is present in population databases (rs199473190, gnomAD 0.01%). This missense change has been observed in individual(s) with long QT syndrome and/or sudden infant death syndrome (PMID: 18596570, 32161207). ClinVar contains an entry for this variant (Variation ID: 67786). 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 serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 18596570). 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. -

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 15, 2023

This variant has been reported in individuals with Long QT Syndrome/Brugada syndrome but the phenotype is not well described (PMID: 34930020, 32161207, 18596570, 25856671). This variant is present in 2/244388 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -

SUDDEN INFANT DEATH SYNDROME Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported as associated with Sudden infant death syndrome in the following publications (PMID:18596570). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
CardioboostCm	Benign	0.0031
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	7.6
DANN	Benign	0.89
DEOGEN2	Benign	0.39	.;.;.;.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.49	.;T;T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.80	.;.;.;.;N;.
PROVEAN	Benign	-0.33	N;N;N;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.86	T;T;T;T;T;T
Sift4G	Benign	0.55	T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;B;B
Vest4		0.67
MVP		0.99
MPC		0.030
ClinPred		0.029	T
GERP RS		-0.91
Varity_R		0.044
gMVP		0.41

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: rs199473190; hg19: chr3-38620965; COSMIC: COSV100351049;