Submissions for variant NM_015378.4(VPS13D):c.12416C>T (p.Ala4139Val)

dbSNP: rs868354311

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV001200859	SCV001338853	likely pathogenic	Autosomal recessive cerebellar ataxia-saccadic intrusion syndrome	2020-04-06	criteria provided, single submitter	clinical testing	This variant isa missense variant absent from gnomAD and predicted as deleterious by PolyPhen-2, LRT and Mutation Taster software. It has a CADD-Phred score of 24.9. It was in trans with another pathogenic variant.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV004556078	SCV005045240	likely pathogenic	Spinocerebellar ataxia type 4	2024-05-17	criteria provided, single submitter	curation	The heterozygous p.Ala4139Val variant in VPS13D was identified by our study, in the compound heterozygous state, along with a pathogenic variant, in one individual with spinocerebellar ataxia 4. Trio exome revealed that this variant was in trans with the other pathogenic variant. This variant has also been reported in one individual with spinocerebellar ataxia 4 (PMID: 35151251), and has been identified in 0.0003% (1/349962) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP (rs868354311)). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has been reported in ClinVar (Variation ID: 932894) and has been interpreted as likely pathogenic by Laboratoire de Genetique Moleculaire, Centre Hospitalier Universitaire de Bordeaux. Of the 2 affected individuals, both were compound heterozygotes that carried a reported pathogenic/likely pathogenic variants in trans, which increases the likelihood that the p.Ala4139Val variant is pathogenic (PMID: 35151251). In vitro functional studies of patient fibroblasts provide some evidence that the p.Ala4139Val variant may impact protein function (PMID: 35151251). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The number of missense variants reported in VPS13D in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive spinocerebellar ataxia 4. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PP2, PS3_Moderate (Richards 2015).