rs199473631
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_000335.5(SCN5A):c.5284G>A(p.Val1762Met) 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V1762V) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 31)
Consequence
SCN5A
NM_000335.5 missense
NM_000335.5 missense
Scores
13
5
2
Clinical Significance
Conservation
PhyloP100: 7.89
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
In a transmembrane_region Helical; Name=S6 of repeat IV (size 22) in uniprot entity SCN5A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000335.5
PM2
Very rare variant in population databases, with high coverage;
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). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. GenCC has associacion of the 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, 0.981
PP5
Variant 3-38551085-C-T is Pathogenic according to our data. Variant chr3-38551085-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 67974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38551085-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN5A | ENST00000413689.6 | c.5287G>A | p.Val1763Met | missense_variant | 28/28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
| SCN5A | ENST00000423572.7 | c.5284G>A | p.Val1762Met | missense_variant | 28/28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 19, 2023 | This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 15485686, 23998552, 30847666). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 15485686, 23998552). 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: 67974). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1763 of the SCN5A protein (p.Val1763Met). - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 05, 2017 | The V1763M pathogenic variant in the SCN5A gene has been reported as a de novo variant in a newborn with congenital LQTS presenting with prenatal bradycardia and postnatal 2:1 atrioventricular block and torsade de pointes ventricular tachycardia (Chang et al., 2004). Similarly, V1763M has been identified as an apparently de novo variant in two unrelated probands with infantile LQTS referred for testing at GeneDx. V1763M was also reported in a 10-year-old child presenting with bradycardia during a viral infection who was subsequently diagnosed with cardiac sinus node dysfunction and found to be compound heterozygous for the V1763M and the D1792N variants in the SCN5A gene (Selly et al., 2012). V1763M has been reported in the published literature in an individual referred for LQTS genetic testing (Tester et al., 2005; Kapplinger et al., 2009), and has also been observed in multiple individuals referred for LQTS testing at GeneDx. The V1763M variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).Although the V1763M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs in the S6 transmembrane domain of repeat IV at a position that is conserved across species. Multiple missense variants in nearby residues (I1758V, L1761F, L1761H, M1766V, M1766L, Y1767C, I1768V) and in the same residue (V1763L) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), supporting the functional importance of this region of the protein. Finally, electrophysiological studies demonstrated the V1763M variant causes persistent inwardcurrent due to altered inactivation kinetics (Chang et al., 2004; Ma et al., 2013). - |
SUDDEN INFANT DEATH SYNDROME Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Robert's Program, Boston Children's Hospital | Oct 01, 2021 | We classify this variant as pathogenic using the following ACMG/AMP criteria: PS3, PS2, PM2 - |
Long QT syndrome 3 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss- or gain of function mechanism (PMID: 29798782). However, some variants simultaneously result in both a loss- and gain of function effect, and have been observed in patients with LQTS, Brugada syndrome or SSS, and patients with a blended phenotype. Additionally, different studies have shown conflicting mechanisms in association with atrial fibrillation (MIM#614022) (PMIDs: 29806494, 19167345, 26798387). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited; however SSS can be caused by recessive variants (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated S6 unit of transmembrane domain IV (PMID: 23998552). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The p.(Val1763Ile) and p.(Val1763Leu) variants have been identified in three affected paediatric cases; moreover, mosaicism and somatic mosaicism has also been reported for the latter (PMIDs: 30059973, 30530868, 27681629). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least five individuals with LQTS or LQT3, a number of whom are paediatric cases (PMIDs: 19716085, 22360817, 27041096, 30059973, 30847666). In addition, this variant was reported to be de novo in two neonates (PMIDs: 15485686,31410243). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Patient dermal cells carrying the p.(Val1763Met) variant which were re-programmed into human-induced pluripotent stem cell cardiomyocytes demonstrated gain of function increased late Na+ current resulting in prolonged action potential duration (APD), and positive shift of steady state inactivation and shortening of the recovery from inactivation of the Na+ current compared to WT cells. The use of mexiletine, a commonly used drug for LQT3 individuals, reduced the late Na+ current and shortened the APD (PMID: 23998552). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (Paternal VCGS #21G000078; Maternal VCGS #15G000098) . (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
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:15485686;PMID:15840476;PMID:16379539;PMID:19716085). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;.;.;.;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;T;T;T;T;T;T;.;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
.;.;.;.;.;M;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D
Polyphen
D;D;.;D;.;D;D;.;.
Vest4
MutPred
0.90
.;.;Loss of catalytic residue at V1763 (P = 0.0261);.;.;Loss of catalytic residue at V1763 (P = 0.0261);.;.;.;
MVP
MPC
1.4
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at