3-38562414-C-T

Variant names:

• chr3-38562414-C-T
• rs483353016
• NM_001099404.2:c.3963+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001099404.2(SCN5A):​c.3963+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCN5A NM_001099404.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.91
• Publications: 2 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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.020327218 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-38562414-C-T is Pathogenic according to our data. Variant chr3-38562414-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38562414-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38562414-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38562414-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38562414-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38562414-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38562414-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38562414-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38562414-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38562414-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38562414-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38562414-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38562414-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38562414-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38562414-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38562414-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 132906.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.3963+1G>A		splice_donor_variant, intron_variant	Intron 22 of 27	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3960+1G>A		splice_donor_variant, intron_variant	Intron 22 of 27	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.3963+1G>A		splice_donor_variant, intron_variant	Intron 22 of 27	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.3960+1G>A		splice_donor_variant, intron_variant	Intron 22 of 27	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000427 AC: 1 AN: 234370 AF XY: 0.00000787

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 FIN exome AF: 0.0000500

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453920 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722306

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.00 AC: 0 AN: 43542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25912

East Asian (EAS) AF: 0.00 AC: 0 AN: 39426

South Asian (SAS) AF: 0.00 AC: 0 AN: 84328

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108566

Other (OTH) AF: 0.00 AC: 0 AN: 60094

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

-

Institute for Genetics of Heart Diseases, University Hospital Muenster

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 132906). Disruption of this splice site has been observed in individuals with SCN5A-related conditions (PMID: 10471492, 20031634, 24972929, 28341781). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 22 of the SCN5A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). -

Brugada syndrome Pathogenic:1

Apr 10, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 3963+1G>A variant in SCN5A had not been reported in individuals with cardiom yopathy, Brugada, or Long QT syndrome and data from large population studies is insufficient to assess the frequency of this variant. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Another varian t as this splice junction (3963+2T>C) has been reported in 2 large families, 1 w ith PCCD and 1 with PCCD and Brugada, and segregated with disease in >20 affecte d relatives (Schott 1999, Probst 2009, Gourraud 2012). Splice and truncating var iants are well-reported in individuals with Brugada syndrome (Human Gene Mutatio n Database). In summary, the predicted impact of this variant supports that it i s likely to be pathogenic, though additional studies are required to fully estab lish its clinical significance. -

Cardiovascular phenotype Pathogenic:1

Nov 02, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3963+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 21 of the SCN5A gene. This alteration has been reported in association with varying arrhythmias, including an individual with progressive cardiac conduction disease (PCCD) and ventricular fibrillation, and has also been detected in a Brugada syndrome (BrS) cohort; however, clinical details were limited (Friedrich C et al. EMBO Mol Med. 2014;6:937-51; Yamagata K et al. Circulation. 2017;135:2255-2270 (reported as IVS23+1G>A)). Another alteration affecting this splice site (c.3963+2T>C) has also been reported in association with PCCD and BrS (Probst V et al. J Am Coll Cardiol. 2003;41:643-52; Probst V et al. Circ Cardiovasc Genet. 2009;2:552-7). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.9
GERP RS		4.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs483353016; hg19: chr3-38603905;