rs753149586

Positions:

• chr3-38581235-C-G
• chr3-38581235-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_000335.5(SCN5A):​c.2924G>C​(p.Arg975Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.244

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 Likely_pathogenic. Variant got 6 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). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. GenCC has associacion of the 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.2924G>C	p.Arg975Pro	missense_variant	17/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.2924G>C	p.Arg975Pro	missense_variant	17/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.2924G>C	p.Arg975Pro	missense_variant	17/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.2924G>C	p.Arg975Pro	missense_variant	17/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 05, 2022

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 975 of the SCN5A protein (p.Arg975Pro). 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 C15"). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
CardioboostCm	Benign	0.00048
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.94	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.0049	D
MutationAssessor	Uncertain	2.9	.;M;.;.;.;M;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.017	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.080	T;T;T;T;T;T;T;T;T
Polyphen		0.90	P;D;.;P;.;P;D;.;.
Vest4		0.64
MutPred		0.64		Loss of MoRF binding (P = 0.0079);Loss of MoRF binding (P = 0.0079);Loss of MoRF binding (P = 0.0079);Loss of MoRF binding (P = 0.0079);Loss of MoRF binding (P = 0.0079);Loss of MoRF binding (P = 0.0079);Loss of MoRF binding (P = 0.0079);Loss of MoRF binding (P = 0.0079);Loss of MoRF binding (P = 0.0079);
MVP		0.92
MPC		0.14
ClinPred		0.96	D
GERP RS		4.6
Varity_R		0.78
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-38622726;