rs1204915217

Variant names:

• chr3-38603712-C-T
• rs1204915217
• NM_001099404.2:c.1890G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001099404.2(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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: SCN5A NM_001099404.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 1.66
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• atrial standstill

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 3-38603712-C-T is Pathogenic according to our data. Variant chr3-38603712-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 505275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000573 AC: 1 AN: 174574 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 30198

American (AMR) AF: 0.0000342 AC: 1 AN: 29246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19808

East Asian (EAS) AF: 0.00 AC: 0 AN: 38696

South Asian (SAS) AF: 0.00 AC: 0 AN: 67546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5172

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1060044

Other (OTH) AF: 0.00 AC: 0 AN: 55766

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiac arrhythmia Pathogenic:2

Oct 29, 2019

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 05, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant alters the conserved c.G at the last nucleotide of exon 12 in the SCN5A gene and is predicted to disrupt mRNA splicing. A functional RNA study has shown that this variant results in retention of intron 10 (PMID: 36197721) with a predicted effect of premature protein truncation (pThr631Valfs*101; PMID: 30059973). This variant has been reported in seven individuals affected with Brugada syndrome (PMID: 20129283, 22885917, 30193851, 32893267, 33221895). This variant has been identified in 1/174574 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SCN5A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Brugada syndrome 1 Pathogenic:1

Oct 05, 2022

Roden Lab, Vanderbilt University Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: in vitro;research

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 -

not provided Pathogenic:1

May 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Brugada syndrome Pathogenic:1

Sep 12, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Cardiovascular phenotype Pathogenic:1

Mar 28, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1890G>A variant (also known as p.T630T), located in coding exon 11 of the SCN5A gene. This variant results from a G to A substitution at nucleotide position 1890. This nucleotide substitution does not change the amino acid 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. This variant was observed in individuals reported to have Brugada syndrome; however, clinical details were limited (Kapplinger JD, Heart Rhythm 2010 Jan; 7:33-46; Chockalingam P, Heart Rhythm 2012 Dec; 9:1986-92; Tarantino A et al. Int J Mol Sci. 2023 Nov;24(23)). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

not specified Uncertain:1

Sep 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

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
PhyloP100		1.7
Mutation Taster		=12/88	disease causing (ClinVar)

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

Other links and lift over

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