rs72549410

chr3-38606058-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001099404.2(SCN5A):c.1231G>A(p.Val411Met) 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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V411V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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, 0.977
• PP5: Variant 3-38606058-C-T is Pathogenic according to our data. Variant chr3-38606058-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 67651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38606058-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.1231G>A	p.Val411Met	missense_variant	10/28	ENST00000413689.6
SCN5A	NM_000335.5	c.1231G>A	p.Val411Met	missense_variant	10/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.1231G>A	p.Val411Met	missense_variant	10/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.1231G>A	p.Val411Met	missense_variant	10/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2019	Reported in several individuals with LQTS, including multiple cases of apparent de novo occurrence, as the variant was not detected in parents (Priori et al., 2000; Tester et al., 2005; Hofman-Bang et al., 2006; Horne et al., 2011; Carrasco et al., 2012; Crotti et al., 2012; Medlock et al., 2012; Stattin et al., 2012; Christiansen et al., 2014; Zhou et al., 2015; Itoh et al., 2016; Vyas et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar as pathogenic (ClinVar Variant ID 67651; Landrum et al., 2016); Published functional studies in cultured cells show that V411M causes a gain of function effect on the sodium channel (Horne et al., 2011; Zhou et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30059973, 31257342, 32161207, 21193062, 22721569, 23098067, 26888838, 27485560, 28588847, 25904541, 26669661, 10961955, 22885918, 15840476, 16712702, 24606995, 19716085, 23158531, 31737537, 32383558) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 04, 2023	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 411 of the SCN5A protein (p.Val411Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 10961955, 15840476, 16712702, 19716085, 21193062, 23098067, 23158531, 24709866). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 67651). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 21193062). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Long QT syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	Jul 23, 2014	- -
Pathogenic, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PS2_Strong, PS3_Moderate, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 26, 2017	- -

Long QT syndrome 3 Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jan 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Feb 08, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Nov 05, 2020	0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene, where missense have been shown to both impair and improve channel current activity (OMIM, PMID: 29806494). (N) 0108 - This gene is known to be associated with both recessive and dominant disease, where recessive disease has few reports and there is no clear genotype-phenotype correlation (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine (exon 10). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools. (P) 0600 - Variant is located in an annotated domain or motif, (S6 of the ion transporter domain I; PMID:21193062). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in multiple de novo individuals with Long QT syndrome (ClinVar, LOVD, PMID:31257342, PMID:21193062). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function, where transfected HEK293 cells demonstrated hyperpolarizing shifts in conductance voltage (PMID:21193062). (P) 1205 - Variant is maternally inherited. The variant is mosaic in this patient's mother at an allele fraction of approximately 12-14%. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 2016

The p.V411M pathogenic mutation (also known as c.1231G>A), located in coding exon 9 of the SCN5A gene, results from a G to A substitution at nucleotide position 1231. The valine at codon 411 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with long QT syndrome (Priori SG et al. Circulation. 2000;102:945-7; Hofman-Bang J et al. Clin Genet. 2006;69:504-11; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Horne AJ et al. Heart Rhythm. 2011;8:770-7; Carrasco JI et al. Rev Esp Cardiol (Engl Ed). 2012;65:1058-9; Stattin EL et al. BMC Cardiovasc Disord. 2012;12:95; Crotti L et al. J Am Coll Cardiol. 2012;60:2515-24; Abrams DJ et al. Circulation. 2014;129:1524-9). This alteration was described as occurring de novo in two unrelated cases, and, in a third case, the alteration was detected in two affected siblings, but not in the unaffected parents (Horne AJ et al. Heart Rhythm. 2011;8:770-7; Carrasco JI et al. Rev Esp Cardiol (Engl Ed). 2012;65:1058-9; Stattin EL et al. BMC Cardiovasc Disord. 2012;12:95). Based on internal structural analysis, this alteration is anticipated to result in a decrease in structural stability (Wu J et al. Science. 2015;350(6267):aad2395In). In addition, in vitro studies have suggested that this alteration may alter channel activities (Horne AJ et al. Heart Rhythm. 2011;8:770-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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:10961955;PMID:15840476;PMID:16712702;PMID:19716085;PMID:21193062). 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	0.90
CardioboostArm	Pathogenic	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.99
MutPred		0.85		Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.82
gMVP		0.94

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: rs72549410; hg19: chr3-38647549;