ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 179 of the PARK7 protein (p.Ala179Thr). This variant is present in population databases (rs71653622, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Parkinson disease (PMID: 18973254). ClinVar contains an entry for this variant (Variation ID: 854701). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect PARK7 function (PMID: 23241025, 28993701). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Variant summary: PARK7 c.535G>A (p.Ala179Thr) results in a non-conservative amino acid change located in the C-terminal H helix (Macedo_2009) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00057 in 254708 control chromosomes (gnomAD and publication data). c.535G>A has been reported in the literature in individuals affected with Autosomal Recessive Early-Onset Parkinson Disease 7, early-onset Alzheimers disease or amyotrophic lateral sclerosis (Macedo_2009, Kenna_2013, Benitez_2016, Diez-Fairen_2018, Giau_2019, Vacchiano_2022, Palomba_2023). These reports do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Early-Onset Parkinson Disease 7. Functional studies reported experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Matsuda_2017, Snchez-Lanzas_2021). The following publications have been ascertained in the context of this evaluation (PMID: 27094865, 29887346, 31182772, 23881933, 27270837, 18973254, 28993701, 36609826, 23241025, 33795807, 35893043). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Identified in the heterozygous state in patients with Parkinson disease; however, a second PARK7 variant was not reported (PMID: 27094865, 19405094); Identified in a patient with Alzheimer's disease; however, variants in other genes that may have been responsible for the phenotype were also reported (PMID: 31182772); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19405094, 23241025, 27270837, 19686841, 29887346, 28993701, 18973254, 37750340, 33795807, 31182772, 35893043, 27094865, 36609826, 23881933)

PARK7: PM2, BP4

BP4