rs149712244
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_003560.4(PLA2G6):c.1799G>A(p.Arg600Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R600W) has been classified as Pathogenic.
Frequency
Consequence
NM_003560.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PLA2G6 | NM_003560.4 | c.1799G>A | p.Arg600Gln | missense_variant | 13/17 | ENST00000332509.8 | NP_003551.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PLA2G6 | ENST00000332509.8 | c.1799G>A | p.Arg600Gln | missense_variant | 13/17 | 1 | NM_003560.4 | ENSP00000333142 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251096Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135860
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461626Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727116
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74344
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 07, 2024 | 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) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 06, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Jun 17, 2016 | - - |
Infantile neuroaxonal dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 05, 2023 | For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 159748). 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. This variant is present in population databases (rs149712244, gnomAD 0.02%). 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). - |
Neurodegeneration with brain iron accumulation 2B Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Mar 06, 2020 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Nov 15, 2017 | - - |
Neurodegeneration with brain iron accumulation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 21, 2023 | 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. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 17, 2021 | 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; Paisán-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. - |
Infantile osteopetrosis with neuroaxonal dysplasia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | 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. - |
PLA2G6-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 15, 2024 | 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. - |
Iron accumulation in brain Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
PLA2G6-associated neurodegeneration Pathogenic:1
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 24, 2023 | 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). - |
Infantile neuroaxonal dystrophy;C1857747:Neurodegeneration with brain iron accumulation 2B;C2751842:Autosomal recessive Parkinson disease 14 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 24, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at