rs756159737

Positions:

• chr3-38581292-ATC-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001099404.2(SCN5A):​c.2865_2866del​(p.Glu955AspfsTer74) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,954 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SCN5A NM_001099404.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 1.55

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 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-38581292-ATC-A is Pathogenic according to our data. Variant chr3-38581292-ATC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 418944.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_000335.5	c.2865_2866del	p.Glu955AspfsTer74	frameshift_variant	17/28	ENST00000423572.7
SCN5A	NM_001099404.2	c.2865_2866del	p.Glu955AspfsTer74	frameshift_variant	17/28	ENST00000413689.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.2865_2866del	p.Glu955AspfsTer74	frameshift_variant	17/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.2865_2866del	p.Glu955AspfsTer74	frameshift_variant	17/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000161 AC: 4 AN: 248468 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134796

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: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460954 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 726596

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Glu955Aspfs*74) in the SCN5A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). This variant is present in population databases (rs756159737, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 418944). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2021	Has been reported as likely pathogenic in an individual with Brugada syndrome in published literature (Campuzano et al., 2020), and in individuals tested at GeneDx; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as pathogenic/likely pathogenic (ClinVar Variant ID# 418944; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 32268277) -

Brugada syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 15, 2023

This variant is predicted to result in loss of protein function through nonsense-mediated or protein truncation. Loss of function is an established mechanism of disease. This prediction has not been confirmed by functional studies. This variant has been observed in individuals with Brugada syndrome (GeneDx) and in one patient with inherited arrhythmogenic syndrome (PMID: 32268277). This variant is present in 4/248468 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 31, 2017

The c.2865_2866delGA pathogenic mutation, located in coding exon 16 of the SCN5A gene, results from a deletion of two nucleotides at nucleotide positions 2865 to 2866, causing a translational frameshift with a predicted alternate stop codon (p.E955Dfs*74). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Cardiac arrhythmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Dec 24, 2019

Variant summary: SCN5A c.2865_2866delGA (p.Glu955AspfsX74) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 248468 control chromosomes. To our knowledge, no occurrence of c.2865_2866delGA in individuals affected with Arrhythmia/Brugada/Long QT syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (one each as Pathogenic, Likely pathogenic and VUS). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Sudden cardiac death;C0151878:Prolonged QT interval Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Apr 02, 2019

The SCN5A Glu955Aspfs*74 variant has not been previously reported in literature but has been identified in individuals with Brugada Syndrome and Restrictive Cardiomyopathy (GeneDx, Pers Comm.; Invitae, Pers Comm.). It is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.000016, and highest sub-population frequency is 0.0035%. We identified this variant in proband diagnosed with both LongQT and infranodal conduction system disease, however this variant did not segregate to an affected family member. Based on these findings we cannot disregard the SCN5A variant. We classify the SCN5A Glu955Aspfs*74 as uncertain significance. Given the gnomAD frequency, this may be further downgraded in future. -

Computational scores

Source: dbNSFP v4.3

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: rs756159737; hg19: chr3-38622783;