VPS4A Gene Curation

Gene-disease assertions not curated here (add link or write note):

Disease	Cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome (CIMDAG syndrome)
Inheritance	Autosomal dominant
Prevalence Possible sources Orphanet Medline Plus Genetics	<1 / 1 000 000 Source: Orphanet
Rapid or full curation?	Rapid Full
ClinGen / GenCC / BabySeq / HGMD / OMIM	ClinGen: None / GenCC: Strong (Invitae); Limited (Ambry) / BabySeq: None /
Clinical Validity Scoring Notes and points	Variant/Case Evidence: c.577_579delTCC, p.Ser193del - Absent gnomAD v4, in frame deletion. De novo in individual 985.382, per table S4 patient is a male with severe ID, not walking, nonverbal, with brain imaging showing atrophy, ventriculomegaly, decreased white matter and thin CC (MRI), central hypotonia and spasticity (PMID: 25356899, 2014) = 1.5 points De novo missense variants in 6 probands (PMID: 33186545, 2020) c.850A>T (p.Arg284Trp) - absent gnomAD v4 and de novo in probands 1, 3, 4, and 5 (1x4 = 4 points) cultured fibroblasts showed significantly enlarged endosomal organelles fig 2 J-L (+0.5) c.850A>G (p.Arg284Gly) - absent gnomAD and de novo in proband 2 (1 point) cultured fibroblasts showed significantly enlarged endosomal organelles fig 2 J-L, and had atypical ESCRT-III protein IST1 accumulates on endosomes (+0.5) c.616G>A (p.Glu206Lys) - absent gnomAD and de novo in proband 6 (1 point) De novo missense variants in 2 probands (PMID: 33186543) = 1.2 points c.850A>T (p.Arg284Trp), Same variant as above but different proband, no author overlap. 1 POINT c.608G>A (p.Gly203Glu) - Absent gnomad v4. 1 POINT They also report a homozygous variant Ala28Val, but this is not part of the curation. Phenotype is similar, perhaps biallelic LOF variants cause a similar disorder. De novo missense variant in 1 proband (PMID: 33460484) c.850 A> T (p.R284W) recurrent variant Segregation Evidence: N/A Case/Control Evidence: N/A Experimental Evidence: N/A Human neuron iPSC cells expressing VPS4A-p.Arg284Trp or -p.Arg284Gly mutants showed no detectable exogenous VPS4A by immunoblotting, and only very sparse expression (<1% of cells) was observed by immunofluorescence, compared to wt VPS4A cell lines. Propose dominant negative effect. Cell culture model = 1 POINT In yeast, Glu228Gln mutation induced a dominant negative vacuolar protein sorting defect(PMID 11563910 - this is per OMIM, I couldnt access the full text). Protein interaction 1 POINT Source: PMID: 25356899; 33186545, 33186543, 33460484
Clinical Validity Points Total	12.5 Source:
Clinical Validity Classification Classifications (pts) Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed	Definitive Source: PMID: 25356899; 33186545, 33186543, 33460484
Molecular Mechanism Mechanisms Loss of function Gain of function Dominant negative Unknown Other	Loss of function
Penetrance options Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID)	High to Complete Source:
Age of Onset options Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID)	Neonatal (Orphanet)
Severity Options Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete. Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high. Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced. Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low. None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.	Moderate to Severe
Clinical Features	Severely impaired psychomotor development and hematologic abnormalities apparent from early infancy. Affected individuals show poor overall growth with microcephaly, impaired intellectual development, poor or absent speech, poor eye contact, and motor problems, such as inability to walk, hypotonia, and spasticity. Brain imaging typically shows cerebral and cerebellar atrophy, thin corpus callosum, and delayed myelination. Eye involvement - congenital cataract, retinal dystrophy Epilepsy Hepatosplenomegaly Sensorineural deafness Growth retardation Sources: PMID: 33186545, 33186543
HPO Terms https://hpo.jax.org/app/	developmental delay, microcephaly, hypotonia, spasticity, cerebral atrophy
Gene SOPs & Notes	LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant
Curation Summary Examples - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity: The severity and expressivity of the disorder is highly variable, even within families. - If multiple conditions associated with the gene: It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited
Case ID, Curator name, Date, Jira ticket link	Grant Fischer - 12/12/2024