rs199473600

chr3-38566498-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PP2 PP3 BP4 BP6

The NM_001099404.2(SCN5A):c.3751G>A(p.Val1251Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7 O:1
• Conservation: PhyloP100: 0.735

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, CardioboostCm, Dann, M_CAP, MutationAssessor, PrimateAI, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate, PROVEAN was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.2870069).
• BP6: Variant 3-38566498-C-T is Benign according to our data. Variant chr3-38566498-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67824.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, not_provided=1, Benign=1, Uncertain_significance=1}. Variant chr3-38566498-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.3751G>A	p.Val1251Met	missense_variant	21/28	ENST00000413689.6
SCN5A	NM_000335.5	c.3748G>A	p.Val1250Met	missense_variant	21/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.3751G>A	p.Val1251Met	missense_variant	21/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.3748G>A	p.Val1250Met	missense_variant	21/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000199 AC: 50 AN: 251448 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135898

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000643 AC: 94 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.0000605 AC XY: 44 AN XY: 727192

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74428

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000124 Hom.: 1

Bravo AF: 0.000570

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000264 AC: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4 Other:1

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 20, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:19841300;PMID:20129283). -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2021	This variant is associated with the following publications: (PMID: 19841300, 20129283, 15851227, 26746457, 25904541) -

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 01, 2021	Variant summary: SCN5A c.3751G>A (p.Val1251Met) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of 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 0.0002 in 251448 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is benign. c.3751G>A has been reported in the literature (example Kapa_2009. These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia/Brugada/Long QT syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in a high throughput patch clamp assay that resulted in re-classification of this variant as benign in accordance with the ACMG classification criteria (example, Glazer_2020). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3; VUS, n=3). Based on the evidence outlined above, the variant was classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 16, 2015	Variant classified as Uncertain Significance - Favor Benign. The p.Val1251Met va riant in SCN5A has not been reported in any other families with DCM. However, it has been identified in a cohort of apparently unaffected African American indiv iduals (1/736 chromosomes; Kapa 2009), as well as in 0.2% (20/10346) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs199473600). Computational prediction tools and conservation analy sis do not provide strong support for or against an impact to the protein. In su mmary, while the clinical significance of the p.Val1251Met variant is uncertain, its frequency suggests that it is more likely to be benign. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 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

Nov 05, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
CardioboostArm	Uncertain	0.60
CardioboostCm	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Pathogenic	0.30
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.3	N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;.;D;.;D;D;.;.
Vest4		0.71
MVP		0.96
MPC		1.3
ClinPred		0.16	T
GERP RS		4.6
Varity_R		0.54
gMVP		0.87

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: rs199473600; hg19: chr3-38607989; COSMIC: COSV61117705;