rs199473078

chr3-38609929-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001099404.2(SCN5A):c.739G>C(p.Val247Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,614,008 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: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 O:1
• Conservation: PhyloP100: 6.17

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 10 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, 11 uncertain in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 3-38609929-C-G is Pathogenic according to our data. Variant chr3-38609929-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68041.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, not_provided=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.739G>C	p.Val247Leu	missense_variant	7/28	ENST00000413689.6
SCN5A	NM_000335.5	c.739G>C	p.Val247Leu	missense_variant	7/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.739G>C	p.Val247Leu	missense_variant	7/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.739G>C	p.Val247Leu	missense_variant	7/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152224 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: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000561 AC: 14 AN: 249540 Hom.: 0 AF XY: 0.0000591 AC XY: 8 AN XY: 135402

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: 0.000510

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461784 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20 AN XY: 727190

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: 0.000525

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2015	The V247L has been reported in one individual referred for LQTS genetic testing and was absent in >2,600 reference alleles (Kapplinger et al., 2009). Detailed clinical information and segregation data were not provided (Kapplinger et al., 2009). The V247L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (I239V, V240M, Q245K) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), supporting the functional importance of this region of the protein. Nevertheless, the V247L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded. -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Oct 19, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2022	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. 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. ClinVar contains an entry for this variant (Variation ID: 68041). This missense change has been observed in individual(s) with clinical suspicion of long QT syndrome (PMID: 19716085). This variant is present in population databases (rs199473078, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 247 of the SCN5A protein (p.Val247Leu). -

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: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	0.77
CardioboostArm	Uncertain	0.69
CardioboostCm	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.092	T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.92
MutPred		0.86		Loss of methylation at K248 (P = 0.0375);Loss of methylation at K248 (P = 0.0375);Loss of methylation at K248 (P = 0.0375);Loss of methylation at K248 (P = 0.0375);Loss of methylation at K248 (P = 0.0375);Loss of methylation at K248 (P = 0.0375);Loss of methylation at K248 (P = 0.0375);Loss of methylation at K248 (P = 0.0375);Loss of methylation at K248 (P = 0.0375);
MVP		0.97
MPC		1.1
ClinPred		0.82	D
GERP RS		5.3
Varity_R		0.86
gMVP		0.96

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: rs199473078; hg19: chr3-38651420;