chr3-38557231-C-G

Position:

• chr3-38557231-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001099404.2(SCN5A):​c.4299G>C​(p.Gly1433=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G1433G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN5A NM_001099404.2 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.38

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.4299G>C	p.Gly1433=	splice_region_variant, synonymous_variant	24/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.4296G>C	p.Gly1432=	splice_region_variant, synonymous_variant	24/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.4299G>C	p.Gly1433=	splice_region_variant, synonymous_variant	24/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.4296G>C	p.Gly1432=	splice_region_variant, synonymous_variant	24/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2017	A novel variant of uncertain significance has been identified in the SCN5A gene. The synonymous G1433G (c.4299 G>C) variant has not been published as pathogenic or been reported as benign to our knowledge. In addition, it is not reported in large population cohorts (Lek et al., 2016). This single nucleotide substitution occurs in the last position of exon 24 and is predicted to destroy the natural donor splice site for intron 24, which may result in abnormal gene splicing. Guanine (G) is conserved at this position across mammals. A different nucleotide substitution at this position (c.4299 G>A, G1433G) has been reported in one individual referred for Brugada syndrome testing; however, no patient-specific clinical data were provided (Kapplinger et al., 2010). However, in the absence of functional mRNA studies, the physiological consequence of the c.4299 G>C variant cannot be precisely determined, and this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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: 201590). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 1433 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 24, which is part of the consensus splice site for this exon. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2023

The c.4299G>C variant (also known as p.G1433G) is located in coding exon 23 of the SCN5A gene. This variant results from a G to C substitution at nucleotide position 4299. This nucleotide substitution does not change the glycine at codon 1433. However, this change occurs in the last base pair of coding exon 23, which makes it likely to have some effect on normal mRNA splicing. This variant, another nucleotide substitution at this position resulting in p.G1433G (c.4299G>A ), have been detected detected in Brudaga syndrome cohorts; however, clinical detail was limited (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Walsh R et al. Genet Med, 2021 Jan;23:47-58; Chen GX et al. EBioMedicine, 2023 Jan;87:104388). A minigene study indicated this variant may impact splicing; however, additional evidence is needed to confirm this finding (O'Neill MJ et al. Circ Genom Precis Med, 2022 Dec;15:e003782). 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.78		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: rs794728935; hg19: chr3-38598722;