Submissions for variant NM_003560.4(PLA2G6):c.2239C>T (p.Arg747Trp)

gnomAD frequency: 0.00003  dbSNP: rs121908687

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000006582	SCV000245524	pathogenic	Autosomal recessive Parkinson disease 14	2014-09-11	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 24-year-old male with adult-onset progressive lower limb weakness/stiffness, spastic gait, hyperthyroidism, diffuse brain atrophy, simialrly affected brother (not tested).
Fulgent Genetics, Fulgent Genetics	RCV000763482	SCV000894265	likely pathogenic	Infantile neuroaxonal dystrophy; Neurodegeneration with brain iron accumulation 2B; Autosomal recessive Parkinson disease 14	2018-10-31	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268312	SCV001447145	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000006582	SCV002764830	pathogenic	Autosomal recessive Parkinson disease 14	2021-06-04	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002512840	SCV003761466	pathogenic	PLA2G6-associated neurodegeneration	2023-01-24	criteria provided, single submitter	curation	The p.Arg747Trp variant in PLA2G6 has been reported at least 6 individuals with PLA2G6-associated neurodegeneration (PMID: 18570303, 27127721, 30868093, 28295203, 35152491, Park_2019), segregated with disease in 2 affected relatives from 2 families (PMID: 28295203, Park_2019), and has been identified in 0.01% (3/23206) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs751225193). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of the 6 affected individuals, all were homozygotes, which increases the likelihood that the p.Arg747Trp variant is pathogenic (PMID: 18570303, 27127721, 30868093, 28295203, 35152491, Park_2019). This variant has also been reported in ClinVar (Variation ID#: 6204) and has been interpreted as pathogenic or likely pathogenic by Fulgent Genetics, Baylor Genetics, Institute of Medical Genetics and Applied Genomics (University Hospital Tübingen), and OMIM. In vitro functional studies provide some evidence that the p.Arg747Trp variant may impact protein function (PMID: 26001724, 26755131, 20886109). However, these types of assays may not accurately represent biological function. Animal models in mice have shown that this variant causes PLA2G6-associated neurodegeneration (PMID: 26755131). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of individuals homozygous for this variant is highly specific for PLA2G6-associated neurodegeneration based on brain iron accumulation on MRI consistent with disease (PMID: 30868093, 28295203). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PM3, PP3, PS3, PP1, PP4 (Richards 2015).
Lifecell International Pvt. Ltd	RCV000006582	SCV003920738	pathogenic	Autosomal recessive Parkinson disease 14		criteria provided, single submitter	clinical testing	A Homozygote Missense variant c.2239C>T in Exon 16 of the PLA2G6 gene that results in the amino acid substitution p.Arg747Trp was identified. The observed variant has a minor allele frequency of 0.0003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic/Likely pathogenicwith a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 6204 as of 2022-12-24). Mutations in the gene have been associated with alterations in PLA2G6 function produce the different disease phenotypes of NBIA/INAD and dystonia-parkinsonism. INAD/NBIA is caused by loss of the ability of PLA2G6 to catalyze fatty acid release from phospholipids (Paisan-Ruiz C et al., 2009; Engel LA et al., 2010). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003507246	SCV004300016	pathogenic	Infantile neuroaxonal dystrophy	2024-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 747 of the PLA2G6 protein (p.Arg747Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with PLA2G6-related conditions (PMID: 18570303, 27127721, 28295203). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6204). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PLA2G6 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PLA2G6 function (PMID: 20886109, 26755131). This variant disrupts the p.Arg747 amino acid residue in PLA2G6. Other variant(s) that disrupt this residue have been observed in individuals with PLA2G6-related conditions (PMID: 35861376; internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000006582	SCV000026765	pathogenic	Autosomal recessive Parkinson disease 14	2009-02-01	no assertion criteria provided	literature only