Submissions for variant NM_007262.5(PARK7):c.535G>A (p.Ala179Thr)

gnomAD frequency: 0.00048  dbSNP: rs71653622

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001059800	SCV001224448	uncertain significance	Autosomal recessive early-onset Parkinson disease 7	2022-09-13	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001059800	SCV001255804	uncertain significance	Autosomal recessive early-onset Parkinson disease 7	2017-04-27	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV001563335	SCV001786256	uncertain significance	not provided	2020-10-14	criteria provided, single submitter	clinical testing	Identified in the heterozygous state in patients with Parkinson disease; however, a second PARK7 variant was not reported (Nuytemans et al., 2009; Benitez et al., 2016); Identified in a patient with Alzheimer's disease; however, variants in other genes that may have been responsible for the phenotype were also reported (Giau et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31182772, 18973254, 28993701, 29887346, 19686841, 27270837, 23241025, 19405094, 27094865)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479275	SCV004222847	uncertain significance	not specified	2023-11-17	criteria provided, single submitter	clinical testing	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.
Breakthrough Genomics, Breakthrough Genomics	RCV001563335	SCV005186322	uncertain significance	not provided		criteria provided, single submitter	not provided