ClinVar Miner

Submissions for variant NM_003560.4(PLA2G6):c.238G>A (p.Ala80Thr)

gnomAD frequency: 0.00001  dbSNP: rs121908685
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000535771 SCV000632025 pathogenic Infantile neuroaxonal dystrophy 2024-08-08 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 80 of the PLA2G6 protein (p.Ala80Thr). This variant is present in population databases (rs121908685, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of PLA2G6-related conditions (PMID: 16783378, 22934738, 30772976, 34622992). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6202). 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%. Experimental studies have shown that this missense change does not substantially affect PLA2G6 function (PMID: 26755131). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000660638 SCV000782761 pathogenic Infantile neuroaxonal dystrophy; Neurodegeneration with brain iron accumulation 2B; Autosomal recessive Parkinson disease 14 2023-05-30 criteria provided, single submitter clinical testing PM3_Strong, PS3_Moderate, PP1_Moderate, PM2
GeneDx RCV001540404 SCV001758287 pathogenic not provided 2022-10-31 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect, as A80T fails to restore wild type protein function and results in significant deficits in neurological function in flies (Mori et al., 2019); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22934738, 30772976, 18799783, 19138334, 16783378, 26755131, 34622992, 35911906, 27196560, 31548400)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002512839 SCV003761028 likely pathogenic PLA2G6-associated neurodegeneration 2023-01-24 criteria provided, single submitter curation The p.Ala80Thr variant in PLA2G6 has been reported in 5 individuals with PLA2G6-associated neurodegeneration (PMID: 16783378, 19138334, 27196560, 30772976, 34622992), segregated with disease in 2 individuals from 1 family (PMID: 30772976), and has been identified in 0.005% (1/18286) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121908685). 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#: 6202) and has been interpreted as pathogenic by GeneDx and OMIM and as a variant of uncertain significance by Mayo Clinic Laboratories (Mayo Clinic) and Invitae. Of the 5 affected individuals, 1 of those was a homozygote, and 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Ala80Thr variant is pathogenic (VariationID: 30371; PMID: 27196560, 30772976). In vitro functional studies provide some evidence that the p.Ala80Thr variant may slightly impact protein function (PMID: 31548400). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. 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: PM2_supporting, PP1, PM3_strong, PS3_supporting (Richards 2015).
Juno Genomics, Hangzhou Juno Genomics, Inc RCV000660638 SCV005415964 pathogenic Infantile neuroaxonal dystrophy; Neurodegeneration with brain iron accumulation 2B; Autosomal recessive Parkinson disease 14 criteria provided, single submitter clinical testing PM2_Supporting+PM3_VeryStrong+PP1_Strong+PP4
Fulgent Genetics, Fulgent Genetics RCV000660638 SCV005663776 pathogenic Infantile neuroaxonal dystrophy; Neurodegeneration with brain iron accumulation 2B; Autosomal recessive Parkinson disease 14 2024-06-24 criteria provided, single submitter clinical testing
OMIM RCV000006580 SCV000026763 pathogenic Neurodegeneration with brain iron accumulation 2B 2008-10-28 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.