chr3-38604062-C-A

Variant names:

• chr3-38604062-C-A
• rs137854606
• NM_001099404.2:c.1540G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3 PP5

The NM_000335.5(SCN5A):​c.1540G>T​(p.Gly514Cys) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G514V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 2.67

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38604061-C-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.829
• PP5: Variant 3-38604062-C-A is Pathogenic according to our data. Variant chr3-38604062-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 9386.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.1540G>T	p.Gly514Cys	missense_variant	Exon 12 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1540G>T	p.Gly514Cys	missense_variant	Exon 12 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1540G>T	p.Gly514Cys	missense_variant	Exon 12 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.1540G>T	p.Gly514Cys	missense_variant	Exon 12 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Cardiac conduction defect, nonprogressive Pathogenic:1

Feb 22, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Conduction system disorder Other:1

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

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Cardiac conduction disease in the following publications (PMID:11234013;PMID:19251209). 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	0.12
CardioboostCm	Benign	0.013
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;.;.;.;.;D;.;.;.
Eigen	Benign	0.13
Eigen_PC	Benign	-0.065
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	0.55	.;N;.;.;.;N;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.020	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.041	D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;.;D;.;D;D;.;.
Vest4		0.39
MutPred		0.74		Loss of methylation at R513 (P = 0.0548);Loss of methylation at R513 (P = 0.0548);Loss of methylation at R513 (P = 0.0548);Loss of methylation at R513 (P = 0.0548);Loss of methylation at R513 (P = 0.0548);Loss of methylation at R513 (P = 0.0548);Loss of methylation at R513 (P = 0.0548);Loss of methylation at R513 (P = 0.0548);Loss of methylation at R513 (P = 0.0548);
MVP		0.94
MPC		1.1
ClinPred		0.94	D
GERP RS		3.8
Varity_R		0.22
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.44		Position offset: -11

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

Publications

LitVar

Other links and lift over

dbSNP: rs137854606; hg19: chr3-38645553;