ClinVar Miner

Submissions for variant NM_003560.4(PLA2G6):c.1674del (p.Leu560fs)

dbSNP: rs587784336
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000147297 SCV000194670 pathogenic Iron accumulation in brain 2014-03-17 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002505128 SCV002816906 pathogenic Infantile neuroaxonal dystrophy; Neurodegeneration with brain iron accumulation 2B; Autosomal recessive Parkinson disease 14 2021-11-05 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002514835 SCV003760982 likely pathogenic PLA2G6-associated neurodegeneration 2023-01-24 criteria provided, single submitter curation The p.Leu560fs variant in PLA2G6 has been reported in 3 individuals, in the compound heterozygous state, with PLA2G6-associated neurodegeneration (PMID: 27378808, 31196701, 24745848) and has been identified in 0.0009% (1/113656) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587784336). 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#: 159742) and has been interpreted as pathogenic by Genetic Services Laboratory (University of Chicago). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 560 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the PLA2G6 gene is an established disease mechanism in autosomal recessive PLA2G6-associated neurodegeneration. 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: PVS1, PM2 (Richards 2015).

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