Submissions for variant NM_003560.4(PLA2G6):c.1799G>A (p.Arg600Gln)

gnomAD frequency: 0.00009  dbSNP: rs149712244

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147303	SCV000194676	pathogenic	Iron accumulation in brain	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000413569	SCV000490726	likely pathogenic	not provided	2024-07-07	criteria provided, single submitter	clinical testing	Observed in apparent homozygous state in patients with infantile neuroaxonal dystrophy in the literature and not observed in homozygous state in controls (PMID: 20619503, 34272103); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35803092, 29472584, 30619057, 20301718, 24745848, 34272103, 33619735, 2668131, 34168672, 36790591, 18443314, 26668131, 20619503, 32613234, 37403138)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000578256	SCV000680340	pathogenic	Neurodegeneration with brain iron accumulation 2B	2017-11-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624119	SCV000741630	pathogenic	Inborn genetic diseases	2021-12-17	criteria provided, single submitter	clinical testing	The c.1799G>A (p.R600Q) alteration is located in exon 13 (coding exon 12) of the PLA2G6 gene. This alteration results from a G to A substitution at nucleotide position 1799, causing the arginine (R) at amino acid position 600 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (11/282490) total alleles studied. The highest observed frequency was 0.02% (6/24928) of African alleles. This alteration has been reported in the homozygous and compound heterozygous states in individuals with PLA2G6-associated neurodegeneration (Davids, 2016; Pais&aacute;n-Ruiz, 2012; Toth-Bencsik, 2021). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000578256	SCV001425305	likely pathogenic	Neurodegeneration with brain iron accumulation 2B	2020-03-06	criteria provided, single submitter	clinical testing	PLA2G6 c.1799G>A (rs149712244) is rare (<0.1%) in a large population dataset (gnomAD: 11/282490 total alleles; 0.0039%; no homozygotes). Four submitters in ClinVar classify this variant as either likely pathogenic or pathogenic (Variation ID: 159748). Three bioinformatics tools queried predict that this substitution would be deleterious. Additionally, bioinformatic analysis predicts that this variant would create a cryptic splice acceptor site in exon 13, which may cause abnormal gene splicing. However, this has not been confirmed experimentally to our knowledge. The arginine residue at this position is conserved across all species accessed. This variant in PLA2G6 has been reported previously in the homozygous state in a patient with infantile onset neuroaxonal dystrophy. We consider the c.1799G>A variant to be likely pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000413569	SCV001448805	likely pathogenic	not provided	2016-06-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000413569	SCV002024664	likely pathogenic	not provided	2022-07-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001849994	SCV002151749	pathogenic	Infantile neuroaxonal dystrophy	2024-03-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 600 of the PLA2G6 protein (p.Arg600Gln). This variant is present in population databases (rs149712244, gnomAD 0.02%). This missense change has been observed in individual(s) with infantile neuroaxonal dystrophy (PMID: 20619503, 26668131, 33619735). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 159748). 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 expected to disrupt PLA2G6 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002505129	SCV002813997	pathogenic	Infantile neuroaxonal dystrophy; Neurodegeneration with brain iron accumulation 2B; Autosomal recessive Parkinson disease 14	2024-06-06	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002514837	SCV003760975	likely pathogenic	PLA2G6-associated neurodegeneration	2023-01-24	criteria provided, single submitter	curation	The p.Arg600Gln variant in PLA2G6 has been reported in 4 individuals with PLA2G6-associated neurodegeneration (PMID: 20619503, 34272103, 26668131, 33619735), and has been identified in 0.02% (6/24928) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs149712244). 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. This variant has also been reported in ClinVar (Variation ID#: 159748) and has been interpreted as pathogenic and likely pathogenic by multiple submitters. Of the 4 affected individuals, 1 was a compound heterozygote that carried reported likely pathogenic variants in trans, and 2 were homozygotes, which increases the likelihood that the p.Arg600Gln variant is pathogenic (VariantID: 265448; PMID: 20619503, 34272103, 26668131). In vitro functional studies provide some evidence that the p.Arg600Gln variant may impact protein function (PMID: 26668131). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg600Trp, has been reported in association with disease in ClinVar, slightly supporting that a change at this position may not be tolerated (Variation ID: 1197568). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PP3, PM5_supporting, PM3_strong, PS3_supporting (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226213	SCV003922902	pathogenic	Neurodegeneration with brain iron accumulation	2023-03-21	criteria provided, single submitter	clinical testing	Variant summary: PLA2G6 c.1799G>A (p.Arg600Gln) results in a conservative amino acid change located in the Patatin-like phospholipase domain (IPR002641) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251096 control chromosomes. c.1799G>A has been reported in the literature in multiple individuals affected with Neurodegeneration With Brain Iron Accumulation/PLA2G6-associated neurodegeneration (PLAN) disorders (example, PMID: 34272103, 33619735, 26668131, 20619503). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV003338422	SCV004047719	likely pathogenic	Infantile osteopetrosis with neuroaxonal dysplasia		criteria provided, single submitter	clinical testing	The missense variant c.1799G>A(p.Arg600Gln) variant has been reported in individuals affected with Infantile neuroaxonal dystrophy 1 and related disorders(Coro et. al., 2012; Davids et. al., 2016; Paisán-Ruiz, Coro et al., 2012). This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The p.Arg600Gln variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.003894% in gnomAD database. The amino acid change p.Arg600Gln in PLA2G6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 600 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. For these reasons, this variant has been classified as Likely Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV001849994	SCV004101480	pathogenic	Infantile neuroaxonal dystrophy		criteria provided, single submitter	clinical testing	The missense variant p.R600Q in PLA2G6 (NM_003560.4) has been observed previously in individuals affected with Neuroaxonal Dystrophy (Paisán et al, 2012). Experimental studies reveal damaging effect (Davids et al, 2016). The p.R600Q variant is observed in 4/16,216 (0.0247%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between arginine and glutamine, which is not likely to impact secondary protein structure as these residues share similar properties.The p.R600Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 600 of PLA2G6 is conserved in all mammalian species. The nucleotide c.1799 in PLA2G6 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. The observed variant was also detected in heterozygous state in the proband's mother.
PreventionGenetics, part of Exact Sciences	RCV003927441	SCV004744446	likely pathogenic	PLA2G6-related disorder	2024-02-15	no assertion criteria provided	clinical testing	The PLA2G6 c.1799G>A variant is predicted to result in the amino acid substitution p.Arg600Gln. This variant has been reported in the compound heterozygous or homozygous state in patients with features consistent with PLA2G6-associated neurodegeneration disorder (Paisan-Ruiz et al. 2012. PubMed ID: 20619503; Davids et al. 2016. PubMed ID: 26668131; Bhardwaj et al. 2021. PubMed ID: 34272103). Another missense variant (c.1798C>T, p. Arg600Trp), which affects the same amino acid, has also been reported to be causative for PLA2G6-associated neurodegeneration with infantile and atypical childhood-onset (Illingworth et al. 2014. PubMed ID: 24745848). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic.