Submissions for variant NM_003560.4(PLA2G6):c.2068G>A (p.Val690Ile)

gnomAD frequency: 0.00041  dbSNP: rs141777179

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147309	SCV000194682	uncertain significance	Iron accumulation in brain	2013-02-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000512748	SCV000609084	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000821691	SCV000962460	uncertain significance	Infantile neuroaxonal dystrophy	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 690 of the PLA2G6 protein (p.Val690Ile). This variant is present in population databases (rs141777179, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PLA2G6-related conditions. ClinVar contains an entry for this variant (Variation ID: 159754). 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 PLA2G6 protein function with a negative predictive value of 80%. 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	RCV001149230	SCV001310169	uncertain significance	PLA2G6-associated neurodegeneration	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Mayo Clinic Laboratories, Mayo Clinic	RCV000512748	SCV001715625	uncertain significance	not provided	2023-05-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000512748	SCV002817850	uncertain significance	not provided	2024-05-23	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000821691	SCV005086333	uncertain significance	Infantile neuroaxonal dystrophy	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with infantile neuroaxonal dystrophy 1 (INAD; MIM#256600), neurodegeneration with brain iron accumulation 2B (NBIA; MIM#610217) and Parkinson disease 14 (MIM#612953). Variants with a loss of function effect result in INAD and NBIA, while missense variants resulting in increased enzyme activity cause Parkinson disease (PMID: 20886109, PMID: 29108286). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (135 heterozygotes, 0 homozygotes). (SP) 0504 - Same amino acid change has been observed in a placental mammal. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. However, the inframe deletion (p.Val691del) of one of two adjacent valine residues (p.Val690-p.Val691) has been reported many times as pathogenic, and was observed in several homozygous individuals with glial mitochondropathy or severe leukodystrophy with additional features (ClinVar, PMID: 27848944, PMID: 27497490). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been consistently reported as a VUS (LOVD, ClinVar), and was observed in a cohort of individuals with Parkinson disease (PMID: 32870915). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Clinical Genetics, Academic Medical Center	RCV000512748	SCV001925826	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000512748	SCV001965275	uncertain significance	not provided		no assertion criteria provided	clinical testing