rs199473301

Positions:

• chr3-38551198-G-A

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.5171C>T​(p.Pro1724Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,461,888 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7 O:1
• Conservation: PhyloP100: 4.93

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 topological_domain Extracellular (size 28) in uniprot entity SCN5A_HUMAN there are 8 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). 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.5174C>T	p.Pro1725Leu	missense_variant	28/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.5171C>T	p.Pro1724Leu	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.5174C>T	p.Pro1725Leu	missense_variant	28/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.5171C>T	p.Pro1724Leu	missense_variant	28/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251170 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135860

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: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461888 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10 AN XY: 727244

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: 0.000112

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1725 of the SCN5A protein (p.Pro1725Leu). This variant is present in population databases (rs199473301, gnomAD 0.01%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 19862833, 26173111). ClinVar contains an entry for this variant (Variation ID: 67962). 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. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cardiac arrhythmia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 29, 2024	This missense variant replaces proline with leucine at codon 1725 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Brugada syndrome (PMID: 26173111, 32268277, DOI:10.1186/s42444-022-00077-9). It has also been reported in an individual affected with long QT syndrome (PMID: 19862833). This variant has been identified in 5/251170 chromosomes 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	May 15, 2023	This missense variant replaces proline with leucine at codon 1725 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Brugada syndrome (PMID: 26173111, 32268277, DOI:10.1186/s42444-022-00077-9). It has also been reported in an individual affected with long QT syndrome (PMID: 19862833). This variant has been identified in 5/251170 chromosomes 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. -

Dilated cardiomyopathy 1E Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

KardioGenetik, Herz- und Diabeteszentrum NRW

Jul 03, 2024

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.5174C>T (p.P1725L) alteration is located in exon 28 (coding exon 27) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 5174, causing the proline (P) at amino acid position 1725 to be replaced by a leucine (L). 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:19862833). 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	Uncertain	0.38
CardioboostCm	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	.;.;.;.;.;M;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-8.0	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	Uncertain	0.013	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.83
MutPred		0.82		.;.;Loss of glycosylation at P1725 (P = 0.0406);.;.;Loss of glycosylation at P1725 (P = 0.0406);.;.;.;
MVP		0.95
MPC		1.5
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.81
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: rs199473301; hg19: chr3-38592689;