ClinVar Miner

Submissions for variant NM_003560.4(PLA2G6):c.2098C>T (p.Gln700Ter)

dbSNP: rs587784346
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000147313 SCV000194686 pathogenic Iron accumulation in brain 2013-02-08 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001781485 SCV002018848 pathogenic not provided 2019-07-09 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001781485 SCV002496745 uncertain significance not provided 2022-07-01 criteria provided, single submitter clinical testing PLA2G6: PM2, PVS1:Moderate, PP4
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002515978 SCV003761472 pathogenic PLA2G6-associated neurodegeneration 2023-01-24 criteria provided, single submitter curation The p.Gln700Ter variant in PLA2G6 has been reported in 2 individuals with PLA2G6-associated neurodegeneration (PMID: 27848944, 23100014) and has been identified in 0.0009% (1/113726) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587784346). 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#: 159758) and has been interpreted as pathogenic by Genetic Services Laboratory (University of Chicago) and PerkinElmer Genomics. Of the 2 affected individuals, both of them were homozygotes, which increases the likelihood that the p.Gln700Ter variant is pathogenic (PMID: 27848944, 23100014). This nonsense variant leads to a premature termination codon at position 700, which is 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, this variant meets criteria to be classified as pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PVS1, PM3, PM2_supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp RCV003507258 SCV004300018 pathogenic Infantile neuroaxonal dystrophy 2024-01-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln700*) in the PLA2G6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PLA2G6 are known to be pathogenic (PMID: 16783378, 18570303, 18799783, 22213678). This variant is present in population databases (rs587784346, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with PLA2G6-related conditions (PMID: 27848944). ClinVar contains an entry for this variant (Variation ID: 159758). For these reasons, this variant has been classified as Pathogenic.

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