rs199473076

chr3-38609950-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_001099404.2(SCN5A):c.718G>A(p.Val240Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,613,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6 O:1
• Conservation: PhyloP100: 6.08

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 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.718G>A	p.Val240Met	missense_variant	7/28	ENST00000413689.6
SCN5A	NM_000335.5	c.718G>A	p.Val240Met	missense_variant	7/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.718G>A	p.Val240Met	missense_variant	7/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.718G>A	p.Val240Met	missense_variant	7/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249168 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135244

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 0.00000821 AC: 12 AN: 1461622 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74374

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiac arrhythmia Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 21, 2023	This missense variant replaces valine with methionine at codon 240 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An in vitro functional study has shown that this variant causes abnormal sodium current recordings in cells derived from a carrier (PMID: 24349418). This variant has been reported in individuals affected with Brugada syndrome (PMID: 20129283, 21273195, 30193851; Mizusawa 2016, PhD dissertation, Universiteit van Amsterdam, https://hdl.handle.net/11245/1.539905) and in a pediatric patient affected with cardiac conduction disease carrying a second truncating SCN5A frameshift variant (PMID: 35052356). This variant has also been reported in an individual affected with unspecified arrhythmia (PMID: 30847666), in an individual affected with long QT syndrome (PMID: 24349418) and in an individual referred for long QT syndrome genetic testing (PMID: 19716085). This variant has been identified in 4/280572 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, 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	Center for Personalized Medicine, Children's Hospital Los Angeles	Mar 15, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces valine with methionine at codon 240 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An in vitro functional study has shown that this variant causes abnormal sodium current recordings in cells derived from a carrier (PMID: 24349418). This variant has been reported in individuals affected with Brugada syndrome (PMID: 20129283, 21273195, 30193851; Mizusawa 2016, PhD dissertation, Universiteit van Amsterdam, https://hdl.handle.net/11245/1.539905) and in a pediatric patient affected with cardiac conduction disease carrying a second truncating SCN5A frameshift variant (PMID: 35052356). This variant has also been reported in an individual affected with unspecified arrhythmia (PMID: 30847666), in an individual affected with long QT syndrome (PMID: 24349418) and in an individual referred for long QT syndrome genetic testing (PMID: 19716085). This variant has been identified in 4/280572 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, 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. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2022	Identified in individuals with Long QT syndrome (LQTS) and referred for LQTS genetic testing (Villarreal-Molina et al., 2021; Kapplinger et al., 2009) and in individuals with Brugada syndrome and referred for Brugada syndrome genetic testing (Berthome et al., 2019; Kapplinger et al., 2010) in published literature; Observed with another variant in trans and both variants were identified in asymptomatic relatives (Villarreal-Molina et al., 2021); LQTS is caused by gain of function variants in the SCN5A channel (NaV1.5), while Brugada syndrome is caused by loss of function variants; as this variant has been identified in individuals with diseases that have different mechanisms of pathogenicity, its clinical significance is uncertain; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In vitro analysis showed that the p.(V240M) variant results in slower inactivation of sodium channels in cardiomyocytes, however some results were not statistically significant (Fatima et al., 2013); This variant is associated with the following publications: (PMID: 21273195, 32180835, 22581653, 28220464, 29728395, 24349418, 27009425, 25815118, 28573431, 28150151, 30755392, 34681161, 32048431, 35052356, 19716085, 30193851, 20129283) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 19, 2023	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 240 of the SCN5A protein (p.Val240Met). This variant is present in population databases (rs199473076, gnomAD 0.009%). This missense change has been observed in individuals with SCN5A-related conditions (PMID: 21273195, 24349418, 30193851, 30755392, 30847666). ClinVar contains an entry for this variant (Variation ID: 68039). 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. 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2020

The c.718G>A (p.V240M) alteration is located in exon 7 (coding exon 6) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 718, causing the valine (V) at amino acid position 240 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital long QT 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 Long QT syndrome in the following publications (PMID:19716085;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	Pathogenic	0.83
CardioboostArm	Uncertain	0.69
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.95
MutPred		0.85		Loss of catalytic residue at V240 (P = 0.0227);Loss of catalytic residue at V240 (P = 0.0227);Loss of catalytic residue at V240 (P = 0.0227);Loss of catalytic residue at V240 (P = 0.0227);Loss of catalytic residue at V240 (P = 0.0227);Loss of catalytic residue at V240 (P = 0.0227);Loss of catalytic residue at V240 (P = 0.0227);Loss of catalytic residue at V240 (P = 0.0227);Loss of catalytic residue at V240 (P = 0.0227);
MVP		0.96
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.87
gMVP		0.97

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: rs199473076; hg19: chr3-38651441;