Submissions for variant NM_174934.4(SCN4B):c.594-2A>G

gnomAD frequency: 0.00002  dbSNP: rs375535030

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000250432	SCV000319921	uncertain significance	Cardiovascular phenotype	2025-01-27	criteria provided, single submitter	clinical testing	The c.594-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 5 in the SCN4B gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. 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. However, the evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
GeneDx	RCV000497442	SCV000589391	uncertain significance	not provided	2018-10-19	criteria provided, single submitter	clinical testing	The c.594-2 A>G variant has not beenpublished as pathogenic or been reported as benign to our knowledge. Thec.594-2 A>G variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000Genomes Consortium et al., 2015; Exome Variant Server). Although this variant is a canonical splice site variant atnucleotide position conserved across species, loss-of-function is not an established mechanism of disease for theSCN4B gene.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854983	SCV002316548	uncertain significance	Long QT syndrome 10	2024-04-01	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the SCN4B gene. It does not directly change the encoded amino acid sequence of the SCN4B protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs375535030, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with SCN4B-related conditions. ClinVar contains an entry for this variant (Variation ID: 264183). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230468	SCV003928730	uncertain significance	not specified	2023-04-04	criteria provided, single submitter	clinical testing	Variant summary: SCN4B c.594-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 251254 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.594-2A>G in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.