3-38597944-A-G

Position:

• chr3-38597944-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_000335.5(SCN5A):​c.2047T>C​(p.Cys683Arg) variant causes a missense change involving the alteration of a 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C683G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46

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]

SCN5A (HGNC:):

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 chr3-38597944-A-C is described in Lovd as [Pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.2047T>C	p.Cys683Arg	missense_variant	14/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.2047T>C	p.Cys683Arg	missense_variant	14/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.2047T>C	p.Cys683Arg	missense_variant	14/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.2047T>C	p.Cys683Arg	missense_variant	14/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

GeneDx

Dec 12, 2017

A variant of uncertain significance has been identified in the SCN5A gene. The C683R variant has not been published as pathogenic or been reported as benign to our knowledge. However, this variant has been reported in one other unrelated individual referred for arrhythmia genetic testing at GeneDx. The C683R variant is not observed in large population cohorts (Lek et al., 2016). The C683R 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, the C683R variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. Lastly, although missense variants at the same residue (C683G, C683S) have been reported in the Human Gene Mutation Database (Stenson et al., 2014), the clinical significance of these variants is unknown. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
CardioboostCm	Benign	0.090
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	.;M;.;.;.;M;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-11	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Polyphen		0.61	P;D;.;P;.;B;P;.;.
Vest4		0.94
MutPred		0.66		Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);
MVP		0.88
MPC		0.89
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.98
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

LitVar

Other links and lift over

dbSNP: rs199473144; hg19: chr3-38639435;