rs199473577

chr3-38603744-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001099404.2(SCN5A):c.1858C>T(p.Arg620Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000287 in 1,533,762 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R620H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 O:1
• Conservation: PhyloP100: 4.58

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.1858C>T	p.Arg620Cys	missense_variant	12/28	ENST00000413689.6
SCN5A	NM_000335.5	c.1858C>T	p.Arg620Cys	missense_variant	12/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.1858C>T	p.Arg620Cys	missense_variant	12/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.1858C>T	p.Arg620Cys	missense_variant	12/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000313 AC: 6 AN: 191644 Hom.: 0 AF XY: 0.0000198 AC XY: 2 AN XY: 101126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000604

Gnomad SAS exome AF: 0.0000592

Gnomad FIN exome AF: 0.0000568

Gnomad NFE exome AF: 0.0000331

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000282 AC: 39 AN: 1381606 Hom.: 0 Cov.: 30 AF XY: 0.0000222 AC XY: 15 AN XY: 676992

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.0000415

Gnomad4 FIN exome AF: 0.0000600

Gnomad4 NFE exome AF: 0.0000271

Gnomad4 OTH exome AF: 0.0000527

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74326

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000427 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000834 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 23, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 620 of the SCN5A protein (p.Arg620Cys). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 24573164, 25904541). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 67694). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 20129283, 24667783, 29728395, 30193851, 32880476). This variant is present in population databases (rs199473577, gnomAD 0.01%). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2022	Functional studies demonstrate that co-expression with wild type did not reduce peak current densities (Hoshi et al., 2014); Reported in association with Brugada syndrome, LQTS, and DCM (Kapplinger et al., 2010; Hazebroek et al., 2015; Kapplinger et al., 2015; Kroncke et al., 2018; Berthome et al., 2019; Verdonschot et al., 2020); Identified in a proband and two siblings with LQTS; all three individuals also harbored a pathogenic KCNQ1 variant (Riur et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30193851, 32880476, 20129283, 24573164, 26383716, 29728395, 30662450, 24667783, 25904541) -

Cardiac arrhythmia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 17, 2023	This missense variant replaces arginine with cysteine at codon 620 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant does not cause a reduction in peak current densities when co-expressed with a wild type protein (PMID: 24573164). This variant has been reported in an individual suspected of having Brugada syndrome (PMID: 20129283). This variant has also been observed in three individuals in a family affected with Long QT syndrome (PMID: 24667783). However, all of these individuals carried a pathogenic variant in KCNQ1, suggesting that this SCN5A variant was likely not the primary cause of disease. This variant has been identified in 7/223000 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 07, 2023	This missense variant replaces arginine with cysteine at codon 620 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant does not cause a reduction in peak current densities when co-expressed with a wild type protein (PMID: 24573164). This variant has been reported in an individual suspected of having Brugada syndrome (PMID: 20129283). This variant has also been observed in three individuals in a family affected with Long QT syndrome (PMID: 24667783). However, all of these individuals carried a pathogenic variant in KCNQ1, suggesting that this SCN5A variant was likely not the primary cause of disease. This variant has been identified in 7/223000 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Brugada 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 Brugada syndrome in the following publications (PMID:20129283). 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	0.073
CardioboostArm	Benign	0.094
CardioboostCm	Benign	0.0041
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.11
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	0.16
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.67	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.41	D
MutationTaster	Benign	0.87	D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.64
Sift	Benign	0.055	T;T;T;T;T;T;T;T;T
Sift4G	Uncertain	0.055	T;T;T;T;T;T;T;T;T
Polyphen		0.91	P;P;.;P;.;P;D;.;.
Vest4		0.70
MVP		0.86
MPC		0.86
ClinPred		0.27	T
GERP RS		3.2
Varity_R		0.098
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs199473577; hg19: chr3-38645235; COSMIC: COSV100349935;