rs199473287

chr3-38551442-G-Achr3-38551442-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_001099404.2(SCN5A):c.4930C>T(p.Arg1644Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1644H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 2.04

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 12 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, 13 uncertain in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38551441-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 3-38551442-G-A is Pathogenic according to our data. Variant chr3-38551442-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67941.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, not_provided=1, Uncertain_significance=1, Likely_pathogenic=1}. Variant chr3-38551442-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.4930C>T	p.Arg1644Cys	missense_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5	c.4927C>T	p.Arg1643Cys	missense_variant	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.4930C>T	p.Arg1644Cys	missense_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.4927C>T	p.Arg1643Cys	missense_variant	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251472 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461882 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1644 of the SCN5A protein (p.Arg1644Cys). This variant is present in population databases (rs199473287, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of long QT syndrome or Brugada syndrome (PMID: 16344400, 16414944, 19716085, 24721456; Invitae). ClinVar contains an entry for this variant (Variation ID: 67941). 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: 16344400). This variant disrupts the p.Arg1644 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8541846, 8620612, 10973849, 19026623, 19841300). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Brugada syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Mar 17, 2023

Well-established functional studies suggest that this variant results in a deleterious effect to the protein that is sufficient to be disease-causing (PMID: 8541846, 8620612, 16344400, 8917568). This variant has been reported in multiple individuals with Brugada syndrome and long QT syndrome (PMID: 16344400, 19411664, 19716085, 25904541, 16414944, 24721456, 28341781, 29691127, 32893267, 33390472, 35956023, 29728395). This variant is located in a well-established functional domain of the protein where other pathogenic or likely pathogenic variants have been described. (PMID: 32893267). This variant is present in 1/251472 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to be deleterious by in silico analysis. This prediction has not been confirmed by functional studies. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2019

The p.R1644C variant (also known as c.4930C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 4930. The arginine at codon 1644 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the DIV/S4 region. This alteration has been reported in association with Brugada syndrome and long QT syndrome (LQTS); however, in several instances, clinical details were limited (Frustaci A et al. Circulation, 2005 Dec;112:3680-7; Napolitano C et al. JAMA, 2005 Dec;294:2975-80; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). One in vitro study indicated this variant may have some impact on channel function (Frustaci A et al. Circulation, 2005 Dec;112:3680-7). Another alteration affecting the same amino acid, p.R1644H (c.4931G>A), has been reported in association with LQTS (Wang Q et al. Hum Mol Genet. 1995;4(9):1603-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, 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:16344400;PMID:16414944;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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostArm	Pathogenic	1.0
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.3	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.94
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		0.87
MutPred		0.96		.;.;Loss of MoRF binding (P = 0.0216);.;.;Loss of MoRF binding (P = 0.0216);.;.;.;
MVP		0.97
MPC		1.7
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.92
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: rs199473287; hg19: chr3-38592933; COSMIC: COSV61131663; COSMIC: COSV61131663;