Submissions for variant NM_032409.3(PINK1):c.1231G>A (p.Gly411Ser)

gnomAD frequency: 0.00146  dbSNP: rs45478900

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000873018	SCV001014936	benign	Autosomal recessive early-onset Parkinson disease 6	2025-01-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001093405	SCV001250365	likely benign	not provided	2024-09-01	criteria provided, single submitter	clinical testing	PINK1: BP4
Illumina Laboratory Services, Illumina	RCV000873018	SCV001256614	uncertain significance	Autosomal recessive early-onset Parkinson disease 6	2017-04-28	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	RCV001093405	SCV002504155	likely benign	not provided	2020-09-10	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004768729	SCV005381047	uncertain significance	not specified	2024-08-15	criteria provided, single submitter	clinical testing	Variant summary: PINK1 c.1231G>A (p.Gly411Ser) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 251026 control chromosomes in the gnomAD database, including 4 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in PINK1 causing Autosomal Recessive Early-Onset Parkinson Disease 6, allowing no conclusion about variant significance. c.1231G>A has been reported in the literature in heterozygous individuals affected with Parkinson Disease. However, it has also been reported in healthy controls and does not segregate with disease in families (e.g. Abou-Sleiman_2006, Benitez_2016, Milanowski_2021, Krohn_2020, Toft_2007, Puschmann_2017, Muldmaa_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Early-Onset Parkinson Disease 6. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced Ub substrate phosphorylation, but no impact on Parkin recruitment to mitochondria (Narendra_2013, Fiesel_2023). The following publications have been ascertained in the context of this evaluation (PMID: 16969854, 27094865, 36469690, 32249012, 33845304, 32740907, 23459931, 27807026, 17172567). ClinVar contains an entry for this variant (Variation ID: 703421). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001093405	SCV001739579	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001093405	SCV001965911	likely benign	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000873018	SCV002574801	not provided	Autosomal recessive early-onset Parkinson disease 6		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003955698	SCV004775174	likely benign	PINK1-related disorder	2024-03-01	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).