ClinVar Miner

Submissions for variant NM_003560.4(PLA2G6):c.1117G>A (p.Gly373Arg) (rs587784327)

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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 RCV000147283 SCV000194656 likely pathogenic Iron accumulation in brain 2013-02-08 criteria provided, single submitter clinical testing
UCLA Clinical Genomics Center, UCLA RCV000199765 SCV000255438 pathogenic Infantile neuroaxonal dystrophy 2014-07-15 criteria provided, single submitter clinical testing
Invitae RCV000199765 SCV000756337 pathogenic Infantile neuroaxonal dystrophy 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 373 of the PLA2G6 protein (p.Gly373Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as either homozygous or in combination with another PLA2G6 variant in individuals affected with infantile neuroaxonal dystrophy or late-onset PLA2G6-associated neurodegeneration (PMID: 19138334, 22934738, 25326637) and segregated with this condition in a family (Invitae external communication). ClinVar contains an entry for this variant (Variation ID: 159728). A mouse model generated by a mutagen that randomly induces point mutations throughout the genome has shown that this missense change results in a significant reduction in calcium responses to ATP in astrocytes (PMID: 19893029, 20947703, 22442204). However, the possibility that there are additional mutations in the neighboring genes of PLA2G6 could not be formally excluded. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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