ClinVar Miner

Submissions for variant NM_018206.6(VPS35):c.2320C>A (p.Leu774Met)

gnomAD frequency: 0.00006  dbSNP: rs192419029
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001092924 SCV001249666 uncertain significance not provided 2021-01-01 criteria provided, single submitter clinical testing
Invitae RCV000577307 SCV001399470 likely pathogenic Parkinson disease 17 2024-01-06 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 774 of the VPS35 protein (p.Leu774Met). This variant is present in population databases (rs192419029, gnomAD 0.01%). This missense change has been observed in individuals with VPS35-related conditions (PMID: 23125461, 28862745; Invitae). ClinVar contains an entry for this variant (Variation ID: 487678). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt VPS35 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect VPS35 function (PMID: 25288323, 26251041). 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.
GeneReviews RCV000577307 SCV000679664 not provided Parkinson disease 17 no assertion provided literature only

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