Neurodegenerative disorders, adult onset

Gene: VPS13C

Green List (high evidence)

Comment on list classification: There are at least 10 unrelated patients available in support of the association of this gene with early-onset Parkinson's disease. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 3 Sep 2026, 12:34 p.m. | Last Modified: 3 Sep 2026, 12:34 p.m.

Panel Version: 9.12

PMID:26942284 (2016) reported three unrelated patients with early-onset parkinsonism carrying biallelic VPS13C loss-of-function variants (a homozygous splice-site variant and two compound heterozygous truncating/splice-disrupting combinations), with rapid disease progression and early cognitive decline. Cellular studies showed VPS13C loss causes mitochondrial fragmentation, reduced mitochondrial membrane potential, increased respiration, and enhanced PINK1/Parkin-dependent mitophagy.

PMID:28862745 (2018) identified an additional sporadic early-onset Parkinson's disease patient with compound heterozygous canonical splice-site VPS13C variants (c.2029+2T>G and c.3215-1G>T), shown by cDNA studies to generate aberrantly spliced transcripts predicting premature protein truncation.

PMID:30452786 (2018) reported an early-onset Parkinson's disease patient identified with a homozygous VPS13C genomic deletion of exons 17–66 (c.1353+3558_9106-7010del; p.Val452_Lys3035del), confirmed by segregation and droplet digital PCR, presenting with parkinsonism and sensorimotor polyneuropathy but normal cognitive status.

PMID:33579389 (2021) identified rare homozygous or compound heterozygous VPS13C missense variants in nine unrelated patients with dementia with Lewy bodies and Parkinson's disease, of which only one patient had homozygous variant. Compound het variants were confirmed to be present in trans state in four unrelated patients including p.Trp395Cys/p.Ala444Pro in index siblings). These variants reduced VPS13C protein expression by up to 90% and abolishing its endosomal/lysosomal localization.

PMID:34875562 (2021) reported two unrelated patients with early-onset Parkinson’s disease carrying three novel VPS13C variants (one homozygous and one compound heterozygous).

Created: 3 Sep 2026, 12:25 p.m. | Last Modified: 3 Sep 2026, 12:25 p.m.

Panel Version: 9.11

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Parkinson disease 23, early onset, OMIM:616840; autosomal recessive early-onset Parkinson disease 23, MONDO:0014796

Publications

• 26942284
• 28862745
• 30452786
• 33579389
• 34875562

I don't know

As discussed with the GMS Neurology Specialist Test Group webex call 11th September 2019: The Specialist Test Group all agreed that there is only enough evidence to rate this gene Amber

Created: 20 Sep 2019, 4:19 p.m. | Last Modified: 20 Sep 2019, 4:19 p.m.

Panel Version: 1.106

Review and rating submitted by Nick Beauchamp (Sheffield Diagnostic genetics Service), on behalf of Yorkshire and North East GLH for GMS Neurology specialist test group.

Created: 23 Jul 2019, 3:51 p.m. | Last Modified: 23 Jul 2019, 3:51 p.m.

Panel Version: 1.74

I don't know

Association with Parkinson disease not clear.

Created: 23 Jul 2019, 3:35 p.m. | Last Modified: 23 Jul 2019, 3:35 p.m.

Panel Version: 1.72

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Parkinson disease 23, autosomal recessive, early onset; 616840

Publications

• 26942284
• 28862745
• 28137300

Variants in this GENE are reported as part of current diagnostic practice