rs199473225

Positions:

• chr3-38560397-G-A
• chr3-38560397-G-C

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.3995C>T​(p.Pro1332Leu) 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. P1332P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 9.91

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 helix (size 24) in uniprot entity SCN5A_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_001099404.2
• 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 4.7729 (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, 0.977
• PP5: Variant 3-38560397-G-A is Pathogenic according to our data. Variant chr3-38560397-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 67844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38560397-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.3995C>T	p.Pro1332Leu	missense_variant	23/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3992C>T	p.Pro1331Leu	missense_variant	23/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.3995C>T	p.Pro1332Leu	missense_variant	23/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.3992C>T	p.Pro1331Leu	missense_variant	23/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2022	Reported in association with LQTS in patients referred to GeneDx and in published literature (Schulze-Bahr et al., 2004; Ruan et al., 2007; Berge et al., 2008; Liu et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a gain-of-function effect as the P1332L variant channel shows a negative voltage shift in steady state inactivation, delayed inactivation, and a more than two-fold increased late sodium current, compared to wild-type channel (Ruan et al., 2007; Liu et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29791480, 24136861, 30662450, 23631430, 17698727, 14676229, 18752142) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2022	ClinVar contains an entry for this variant (Variation ID: 67844). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 17698727). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with long QT syndrome (LQTS) (PMID: 14676229, 17698727, 18752142, 23631430). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1332 of the SCN5A protein (p.Pro1332Leu). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 04, 2022	- -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 03, 2020

Variant summary: SCN5A c.3995C>T (p.Pro1332Leu) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251040 control chromosomes (gnomAD). c.3995C>T has been reported in the literature in multiple individuals affected with Long QT Syndrome and Brugada Syndrome (e.g. Ruan_2007, Riuro_2015, Liu_2018, Shimizu_2019). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated slower inactivation and prominent late Na+ currents (Ruan_2007, Liu_2018). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2023

The p.P1332L pathogenic mutation (also known as c.3995C>T), located in coding exon 22 of the SCN5A gene, results from a C to T substitution at nucleotide position 3995. The proline at codon 1332 is replaced by leucine, an amino acid with similar properties. This alteration was reported to occur de novo in a patient with long QT syndrome (LQTS) presenting first with fetal bradycardia and tachycardia as well as third degree AV block, prolonged QT interval, and non-sustained polymorphic ventricular tachycardia as an infant (Schulze-Bahr E et al. Heart. 2004;90:13-6). Another study reported this alteration in two unrelated individuals with LQTS, and in vitro studies indicated abnormal ion channel function as a result of this alteration (Ruan Y et al. Circulation. 2007;116:1137-44). This alteration was also reported in a Brugada syndrome cohort; howevver, clinical details were limited (Kapplinger JD et al. Heart Rhythm. 2010;7:33-46). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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:14676229;PMID:15136511;PMID:17698727;PMID:18752142;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	0.98
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	.;.;.;.;.;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-9.7	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	Benign	0.085	T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.97
MutPred		0.86		Gain of MoRF binding (P = 0.3123);.;Gain of MoRF binding (P = 0.3123);Gain of MoRF binding (P = 0.3123);.;Gain of MoRF binding (P = 0.3123);.;.;.;
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.95
gMVP		0.99

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: rs199473225; hg19: chr3-38601888; COSMIC: COSV104658844;