rs1204915217

Positions:

• chr3-38603712-C-T

Variant summary

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

The NM_000335.5(SCN5A):​c.1890G>A​(p.Thr630Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 1,355,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: SCN5A NM_000335.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 1.66

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]

SCN5A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-38603712-C-T is Pathogenic according to our data. Variant chr3-38603712-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505275.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=4}. Variant chr3-38603712-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.1890G>A	p.Thr630Thr	splice_region_variant, synonymous_variant	12/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1890G>A	p.Thr630Thr	splice_region_variant, synonymous_variant	12/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1890G>A	p.Thr630Thr	splice_region_variant, synonymous_variant	12/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.1890G>A	p.Thr630Thr	splice_region_variant, synonymous_variant	12/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000573 AC: 1 AN: 174574 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 92352

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000475

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000148 AC: 2 AN: 1355366 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 661718

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000342

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: 9.43e-7

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

Brugada syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

in vitro;research

Roden Lab, Vanderbilt University Medical Center

Oct 05, 2022

The synonymous SCN5A variant c.1890G>A was observed in 1 case of Brugada Syndrome and is absent from large population databases (PMID: 32893267). The variant is predicted to alter RNA splicing. A minigene functional assay showed aberrant splicing induced by the variant. These findings support the classification of this variant as Likely Pathogenic -

Brugada syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 12, 2024

The c.1890G>A (p.Thr630=) synonymous variant in the SCN5A gene is located at the last nucleotide of exon 12. It is a part of the consensus splice site and is predicted to result in donor loss (SpliceAI delta score: 0.67) leading to alternative splicing and an aberrant or disrupted protein product. This variant has been reported in five individuals with Brugada syndrome (PMID: 20129283, 22885917, 30193851, 33221895). A functional study with minigene assay demonstrated aberrantly spliced transcript with intron retention and the disruptive impact of this variant (PMID: 36197721). Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 30193851, 20129283). This variant is rare in the general population database, gnomAD (1/174574). This variant is reported in ClinVar (ID:505275). Therefore, the c.1890G>A (p.Thr630=) variant in the SCN5A gene is classified as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

This sequence change affects codon 630 of the SCN5A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SCN5A protein. This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.005%). This variant has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 20129283, 22885917, 30193851, 33221895). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 505275). 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). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2024

The c.1890G>A (p.T630T) alteration is located in exon 12 (coding exon 11) of the SCN5A gene. This alteration consists of a G to A substitution at nucleotide position 1890. This nucleotide substitution does not change the threonine at codon 630. However, this change occurs in the last base pair of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. Based on data from gnomAD, the A allele has an overall frequency of 0.001% (1/174574) total alleles studied. The highest observed frequency was 0.005% (1/21048) of Latino alleles. This variant was observed in individuals reported to have Brugada syndrome; however, clinical details were limited (Kapplinger, 2010; Chockalingam, 2012). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as likely pathogenic. -

Cardiac arrhythmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Oct 29, 2019

Variant summary: SCN5A c.1890G>A (p.Thr630Thr) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts that the variant abolishes a 5' splicing donor site, while four predict that the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.7e-06 in 174574 control chromosomes (gnomAD). c.1890G>A has been reported in the literature in individuals affected with Arrhythmia [e.g. Kapplinger_2010 (Brugada Syndrome), Chockalingham_2012, Baruteau_2018]. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions (evaluation after 2014) cites the variant once as likely pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 21, 2016

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr630Thr variant in SCN5A has been reported in 4 individuals with Brugada syndrome (Kapp linger 2010, Chockalingam 2012) and was absent from large population studies. Th is variant is located in the last three bases of the exon, which is part of the 5? splice region. Computational predictions suggest a possible effect but functi onal assays would be needed to confirm this. Splice variants often lead to loss of function, which is an established mechanism for this gene for Brugada syndrom e. In summary, the absence from large populations, occurrence in several proband s with a consistent phenotype and location of the variant provide some support f or a role in disease; however, without additional evidence the clinical signific ance of the p.Thr630Thr variant remains uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.67		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1204915217; hg19: chr3-38645203; COSMIC: COSV100347734;