ClinVar Miner

Submissions for variant NM_015378.4(VPS13D):c.941+3A>G

gnomAD frequency: 0.00002  dbSNP: rs372431023
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Kids Neuroscience Centre, Sydney Children's Hospitals Network RCV001726516 SCV001571503 likely pathogenic Autosomal recessive cerebellar ataxia-saccadic intrusion syndrome criteria provided, single submitter clinical testing The c.941+3A>G variant results in two detected abnormal splicing events: (1) Exon-9 skipping (p.Gln282Profs*11), (2)Intron-9 retention (p.Asn314Lysfs*2). All abnormal splicing events induced by the c.941+3A>G variant create a frameshift and premature termination codon. The abnormally spliced VPS13D transcripts are predicted to be targeted for nonsense -mediated decay. Any VPS13D transcripts escaping nonsense-mediated decay encode VPS13D proteins that are severely truncated N-terminal peptides (usually 4388 amino acids) and likely to be dysfunctional/non-functional/unstable.
GeneDx RCV004794536 SCV005414927 pathogenic not provided 2024-05-22 criteria provided, single submitter clinical testing RNA studies demonstrate leaky splicing resulting in an out of-frame transcript with skipping of exon 9 (PMID: 36768210); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36768210, 29604224, 34906502)
Labcorp Genetics (formerly Invitae), Labcorp RCV004794536 SCV005706315 likely pathogenic not provided 2024-02-20 criteria provided, single submitter clinical testing This sequence change falls in intron 9 of the VPS13D gene. It does not directly change the encoded amino acid sequence of the VPS13D protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of spinocerebellar ataxia (PMID: 29604224, 36768210). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1064611). Studies have shown that this variant does not significantly alter or has an unclear effect on VPS13D gene expression (PMID: 36768210). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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