3-38550646-T-C

Position:

• chr3-38550646-T-C

Variant summary

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

The NM_000335.5(SCN5A):​c.5723A>G​(p.Gln1908Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,698 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 O:1
• Conservation: PhyloP100: 8.02

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]

SCN5A (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain IQ (size 29) in uniprot entity SCN5A_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) 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). 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, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.5726A>G	p.Gln1909Arg	missense_variant	28/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.5723A>G	p.Gln1908Arg	missense_variant	28/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.5726A>G	p.Gln1909Arg	missense_variant	28/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.5723A>G	p.Gln1908Arg	missense_variant	28/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461698 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727126

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: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiac arrhythmia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 03, 2023	This missense variant replaces glutamine with arginine at codon 1909 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental electrophysiological studies using in vitro expression systems have shown this variant increases late sodium current (PMID: 25370050, 25757662, 25904541, 28087622, 28734073). However, clinical relevance of this observation is not clear. This variant has been reported in an individual affected with long QT syndrome (PMID: 19841300), in an individual affected with sudden infant death syndrome (PMID: 25757662), and in an individual referred for long QT syndrome genetic testing (PMID: 15840476). This variant has also been reported in an individual with normal QT interval (PMID: 26159999). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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	Color Diagnostics, LLC DBA Color Health	Mar 20, 2023	This missense variant replaces glutamine with arginine at codon 1909 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental electrophysiological studies using in vitro expression systems have shown this variant increases late sodium current (PMID: 25370050, 25757662, 25904541, 28087622, 28734073). However, clinical relevance of this observation is not clear. This variant has been reported in an individual affected with long QT syndrome (PMID: 19841300), in an individual affected with sudden infant death syndrome (PMID: 25757662), and in an individual referred for long QT syndrome genetic testing (PMID: 15840476). This variant has also been reported in an individual with normal QT interval (PMID: 26159999). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 28, 2012

p.Gln1909Arg (CAG>CGG): c.5726 A>G in exon 28 of the SCN5A gene (NM_198056.2) The Gln1909Arg mutation in the SCN5A gene has also been reported previously in one individual with LQTS, and this mutation was absent from 1,688 control alleles (Tester D et al., 2005). The NHLBI ESP Exome Variant Server reports Gln1909Arg was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Gln1909Arg results in a non-conservative amino acid substitution of a neutral, polar Glutamine with a positively charged Arginine at a residue that is conserved across species. In silico analysis predicts Gln1909Arg is probably damaging to the protein structure/function. In addition, a mutation in a nearby codon (Arg1913His) has also been reported in association with LQTS, supporting the functional importance of this region of the protein. In summary, Gln1909Arg in the SCN5A gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s). -

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 1909 of the SCN5A protein (p.Gln1909Arg). 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: 19841300). ClinVar contains an entry for this variant (Variation ID: 68008). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 25757662, 28087622, 28734073). 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

May 23, 2024

The c.5726A>G (p.Q1909R) alteration is located in exon 28 (coding exon 27) of the SCN5A gene. This alteration results from a A to G substitution at nucleotide position 5726, causing the glutamine (Q) at amino acid position 1909 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). One individual with a definite diagnosis of Long QT syndrome was observed to have this variant, and it was not detected in 1300 healthy controls (Kapa, 2009). This variant was also reported in a child with SIDS (Winkel, 2015). This amino acid position is highly conserved in available vertebrate species. While this variant occurs at the interface with Calmodulin, a protein central in regulation of heart rhythm, internal structural analysis indicates this variant may not be sufficiently destabilizing to suggest pathogenicity (Wang, 2012; Gabelli, 2014; Ambry internal data). In vitro functional data suggests that this variant may interfere with channel gating (Winkel, 2015). This alteration is predicted to be deleterious by in silico analysis. 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:15840476;PMID:19841300). 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	0.91
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	.;.;.;.;.;H;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.91
MutPred		0.90		.;.;Gain of helix (P = 0.0022);.;.;Gain of helix (P = 0.0022);.;.;.;
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.96
gMVP		0.98

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: rs199473326; hg19: chr3-38592137; COSMIC: COSV61116249; COSMIC: COSV61116249;