rs1057520531

Positions:

• chr3-38556436-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001099404.2(SCN5A):​c.4437+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000349 in 1,431,962 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SCN5A NM_001099404.2 splice_donor_5th_base, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• Conservation: PhyloP100: 7.91

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-38556436-C-T is Pathogenic according to our data. Variant chr3-38556436-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 379225.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_000335.5	c.4434+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000423572.7
SCN5A	NM_001099404.2	c.4437+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000413689.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.4437+5G>A		splice_donor_5th_base_variant, intron_variant		5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.4434+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000349 AC: 5 AN: 1431962 Hom.: 0 Cov.: 36 AF XY: 0.00000564 AC XY: 4 AN XY: 709088

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: 0.00

Gnomad4 NFE exome AF: 0.00000365

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Brugada syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Mar 11, 2019	- -
Likely pathogenic, criteria provided, single submitter	in vitro;research	Roden Lab, Vanderbilt University Medical Center	Oct 05, 2022	The SCN5A variant c.4437+5G>A was observed in 2 cases of Brugada Syndrome and is absent from large population databases (PMID: 32893267). The variant is predicted to alter mRNA splicing. Functional investigations in an iPSC-CM model showed pseudoexon inclusion induced by the edited allele that introduced a frameshift in the predominant aberrantly spliced product. These findings collectively support a Likely Pathogenic classification. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2023	Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect as the variant results in the use of a cryptic spice donor site downstream of the natural donor site, leading to a frameshift (O'Neill et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21273195, 33221895, 25525159, 19251209, 20129283, 21321465, 29709101, 29709244, 36197721, 35124229) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	This sequence change falls in intron 25 of the SCN5A gene. It does not directly change the encoded amino acid sequence of the SCN5A protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of SCN5A-related conditions (PMID: 19251209, 21321465, 33221895, 35124229, 36578016; Invitae). ClinVar contains an entry for this variant (Variation ID: 379225). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 36197721). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2022

The c.4437+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 24 in the SCN5A gene. This variant has been seen in several Brugada syndrome (BrS) cohorts (Ciconte G et al. Eur Heart J, 2021 03;42:1082-1090; Amin AS et al. Int J Cardiol, 2018 Sep;266:128-132; Nakajima T et al. Int Heart J, 2011;52:27-31; Meregalli PG et al. Heart Rhythm, 2009 Mar;6:341-8). This nucleotide position is highly conserved in available vertebrate species. This alteration is located within a U12-type intron and in silico tools are not reliable predictors of splice sites in this type of intron. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Long QT syndrome 3 Uncertain:1

Uncertain significance, no assertion criteria provided

research

Division of Human Genetics, Children's Hospital of Philadelphia

Aug 23, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	30
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.50		Position offset: -27
DS_DL_spliceai		0.34		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057520531; hg19: chr3-38597927; COSMIC: COSV61119095; COSMIC: COSV61119095;