Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Illumina Laboratory Services, |
RCV000779372 | SCV000915973 | uncertain significance | PLA2G6-associated neurodegeneration | 2018-11-26 | criteria provided, single submitter | clinical testing | The PLA2G6 c.1904G>A (p.Arg635Gln) missense variant has been reported in a compound heterozygous state in three Japanese individuals with early-onset (<30 years) parkinsonism with dementia and frontotemporal lobar atrophy (Yoshino et al. 2010). Two of these individuals were brothers, and all three shared a common haplotype. This variant was also reported in a homozygous state in a Japanese individual with adult-onset (age 66 years) spastic paraplegia with parkinsonism (Koh et al. 2018). This individual had an older sibling with a similar phenotype, but the sibling did not undergo genetic testing. The p.Arg635Gln variant was identified in one out of 2722 Japanese control chromosomes and is reported at a frequency of 0.000738 in the East Asian population of the Exome Aggregation Consortium. This frequency is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. The evidence for this variant is limited. The p.Arg635Gln variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for PLA2G6-associated neurodegeneration. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
Gene |
RCV002273936 | SCV002559575 | likely pathogenic | not provided | 2022-02-11 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32183746, 26196026, 25601130, 30302010, 20938027, 32771225) |
Fulgent Genetics, |
RCV002477008 | SCV002793301 | uncertain significance | Infantile neuroaxonal dystrophy; Neurodegeneration with brain iron accumulation 2B; Autosomal recessive Parkinson disease 14 | 2021-11-02 | criteria provided, single submitter | clinical testing | |
Invitae | RCV002513186 | SCV003519119 | pathogenic | Infantile neuroaxonal dystrophy | 2024-01-18 | 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 635 of the PLA2G6 protein (p.Arg635Gln). This variant is present in population databases (rs387906863, gnomAD 0.009%). This missense change has been observed in individuals with early onset Parkinson disease (PMID: 20938027, 32771225). ClinVar contains an entry for this variant (Variation ID: 30366). 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. |
Broad Institute Rare Disease Group, |
RCV000779372 | SCV003760971 | likely pathogenic | PLA2G6-associated neurodegeneration | 2023-01-24 | criteria provided, single submitter | curation | The p.Arg635Gln variant in PLA2G6 has been reported in 8 individuals with PLA2G6-associated neurodegeneration (PMID: 20938027, 30302010, 32771225), segregated with disease in 1 affected relative from 1 family (PMID: 20938027), and has been identified in 0.009% (1/11702) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs387906863). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 30366) and has been interpreted as a variant of uncertain significance by Illumina Laboratory Services (Illumina) and as pathogenic by OMIM. Of the 8 affected individuals, 1 of those was a homozygote, 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, and 1 was a compound heterozygote that carried a variant of uncertain significance in trans, which increases the likelihood that the p.Gly653Ser variant is pathogenic (PMID: 20938027, 30302010, 32771225). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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, PM2_supporting, PM3_strong (Richards 2015). |
OMIM | RCV000023314 | SCV000044605 | pathogenic | Autosomal recessive Parkinson disease 14 | 2010-10-12 | no assertion criteria provided | literature only |