rs199473059

chr3-38630330-C-Gchr3-38630330-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 5P and 12B. PM1 PM2 PP2 BP4_Strong BP6_Very_Strong

The NM_001099404.2(SCN5A):c.373G>C(p.Val125Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000924 in 1,612,952 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V125M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000097 (1 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 3.95

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 Benign. Variant got -7 ACMG points.

• PM1: In a helix (size 7) in uniprot entity SCN5A_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• BP4: Computational evidence support a benign effect (MetaRNN=0.06334475).
• BP6: Variant 3-38630330-C-G is Benign according to our data. Variant chr3-38630330-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 67821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38630330-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.373G>C	p.Val125Leu	missense_variant	3/28	ENST00000413689.6
SCN5A	NM_000335.5	c.373G>C	p.Val125Leu	missense_variant	3/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.373G>C	p.Val125Leu	missense_variant	3/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.373G>C	p.Val125Leu	missense_variant	3/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152244 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000217 AC: 54 AN: 249290 Hom.: 1 AF XY: 0.000281 AC XY: 38 AN XY: 135234

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: 0.00167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000972 AC: 142 AN: 1460590 Hom.: 1 Cov.: 29 AF XY: 0.000136 AC XY: 99 AN XY: 726730

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: 0.00135

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.0000459 AC: 7 AN: 152362 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74506

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.000256 AC: 31

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 28988457, 23805106, 28150151, 29396286, 25351510, 19716085, 15840476) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 08, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Apr 08, 2021

Variant summary: SCN5A c.373G>C (p.Val125Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 249290 control chromosomes, predominantly at a frequency of 0.0017 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 17-fold the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.373G>C has been reported in the literature in individuals with suspected long QT syndrome (e.g.Tester_2005) . These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (e.g. Gutter_2013). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely benign (n=2) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Brugada syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 23, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cardiac arrhythmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 03, 2018

- -

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: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	Benign	0.34
CardioboostArm	Benign	0.069
CardioboostCm	Benign	0.026
BayesDel_addAF	Benign	0.0086	T
BayesDel_noAF	Pathogenic	0.22
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.063	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.38	D
MutationTaster	Benign	0.92	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.030	D;D;D;D;D;D;D;D;D;T
Polyphen		0.26	B;P;.;B;.;B;B;.;.;.
Vest4		0.50
MutPred		0.77		Loss of methylation at K126 (P = 0.0351);Loss of methylation at K126 (P = 0.0351);Loss of methylation at K126 (P = 0.0351);Loss of methylation at K126 (P = 0.0351);Loss of methylation at K126 (P = 0.0351);Loss of methylation at K126 (P = 0.0351);Loss of methylation at K126 (P = 0.0351);Loss of methylation at K126 (P = 0.0351);Loss of methylation at K126 (P = 0.0351);Loss of methylation at K126 (P = 0.0351);
MVP		0.94
MPC		0.97
ClinPred		0.17	T
GERP RS		5.1
Varity_R		0.30
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199473059; hg19: chr3-38671821;