ClinVar Miner

Submissions for variant NM_001128159.3(VPS53):c.1556+5G>A

gnomAD frequency: 0.00001  dbSNP: rs587777466
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002298475 SCV002598685 pathogenic Pontoneocerebellar hypoplasia 2022-09-01 criteria provided, single submitter clinical testing Variant summary: VPS53 c.1556+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site and two predict it weakens a 5' donor site. Experimental evidence supports these predictions indicating the variant generates an aberrant/unstable transcript (Feinstein_2014). The variant was absent in 251280 control chromosomes (gnomAD). c.1556+5G>A has been reported in the literature in multiple compound heterozygous individuals affected with Pontocerebellar Hypoplasia, Type 2E (example, Feinstein_2014 and Hady-Cohen_2018). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000128408 SCV002788405 likely pathogenic Pontocerebellar hypoplasia type 2E 2021-11-12 criteria provided, single submitter clinical testing
Invitae RCV003556173 SCV004296447 pathogenic not provided 2023-10-17 criteria provided, single submitter clinical testing This sequence change falls in intron 14 of the VPS53 gene. It does not directly change the encoded amino acid sequence of the VPS53 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 progressive cerebello-cerebral atrophy (PMID: 24577744, 30100179). It is commonly reported in individuals of Moroccan Jewish ancestry (PMID: 24577744, 30100179). ClinVar contains an entry for this variant (Variation ID: 139445). 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. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000128408 SCV000172014 pathogenic Pontocerebellar hypoplasia type 2E 2014-05-01 no assertion criteria provided literature only

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