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

dbSNP: rs587784327

Total submissions: 4

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199765	SCV000756337	pathogenic	Infantile neuroaxonal dystrophy	2018-11-26	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (ExAC no frequency). 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. 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. For these reasons, this variant has been classified as Pathogenic. 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.
Ambry Genetics	RCV001266410	SCV001444584	pathogenic	Inborn genetic diseases	2021-11-22	criteria provided, single submitter	clinical testing	The c.1117G>A (p.G373R) alteration is located in exon 8 (coding exon 7) of the PLA2G6 gene. This alteration results from a G to A substitution at nucleotide position 1117, causing the glycine (G) at amino acid position 373 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). A Chinese patient, reported to have the p.G373R and p.K545E alterations, was diagnosed with infantile neuroaxonal dystrophy. The patient was free of symptoms at birth and achieved normal developmental milestones before onset of symptoms at 7 months, which rapidly progressed to a vegetative state by 5 years. Brain MRI imaging showed cerebellar atrophy and neuropathology showed the typical presence of axonal swelling and spheroid bodies (Wu, 2009). Another Chinese patient with late onset PLA2G6-related neurodegeneration was confirmed to be compound heterozygous with this alteration and the p.I689F alteration based on parental testing. Age of onset was at 14 years with gait disturbance followed by mental and behavioral problems after two years and a brain MRI showing cerebellar atrophy and progressive iron accumulation in the globus pallidus and substantia nigra (Zhang, 2013). The p.G373R alteration was in trans with p.S504L in another Chinese patient with PLA2G6-related neurodegeneration. His brother was also affected but had a milder phenotype (Chen, 2018). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.