Submissions for variant NM_003560.4(PLA2G6):c.2370_2371del (p.Tyr790_Glu791delinsTer)

gnomAD frequency: 0.00003  dbSNP: rs587784353

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147322	SCV000194695	pathogenic	Iron accumulation in brain	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000255768	SCV000321927	pathogenic	not provided	2022-01-11	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 17 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16783378, 18799783, 29915382)
Baylor Genetics	RCV000006578	SCV001163822	pathogenic	Infantile neuroaxonal dystrophy		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000006578	SCV001411590	pathogenic	Infantile neuroaxonal dystrophy	2024-07-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr790*) in the PLA2G6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acid(s) of the PLA2G6 protein. This variant is present in population databases (rs587784353, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with clinical features of PLA2G6-related conditions (PMID: 16783378, 27378808, 29915382; Invitae). ClinVar contains an entry for this variant (Variation ID: 6201). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PLA2G6 function (PMID: 20886109). For these reasons, this variant has been classified as Pathogenic.
Centogene AG - the Rare Disease Company	RCV000006578	SCV002059521	pathogenic	Infantile neuroaxonal dystrophy	2020-01-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504755	SCV002805731	pathogenic	Infantile neuroaxonal dystrophy; Neurodegeneration with brain iron accumulation 2B; Autosomal recessive Parkinson disease 14	2024-03-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512837	SCV003551608	pathogenic	Inborn genetic diseases	2021-01-07	criteria provided, single submitter	clinical testing	The c.2370_2371delTG (p.Y790*) alteration, located in exon 17 (coding exon 16) of the PLA2G6 gene, consists of a deletion of 2 nucleotides from position 2370 to 2371. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 790. This alteration occurs at the 3' terminus of the PLA2G6 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 17/806 (2%) of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function. Based on data from the Genome Aggregation Database (gnomAD) database, the PLA2G6 c.2370_2371delTG alteration was observed in 0.0033% (8/242472) of total alleles studied. The p.Y790* alteration has been reported in the homozygous and compound heterozygous state in multiple patients with PLA2G6-associated neurodegenerative disorders (Morgan, 2006; Gregory, 2008; Paisán-Ruiz, 2012; Sun, 2019). Functional studies demonstrate that the p.Y790* alteration has less than 10% catalytic activity in two substrates compared to wild type (Engel, 2010). Based on the available evidence, this alteration is classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002512838	SCV003761456	likely pathogenic	PLA2G6-associated neurodegeneration	2023-01-24	criteria provided, single submitter	curation	The c.2370_2371delTG variant in PLA2G6 has been reported in at least 5 individuals with PLA2G6-associated neurodegeneration (PMID: 18799783, 20619503, 29915382, 16783378), and has been identified in 0.007% (1/15202) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587784353). 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#: 6201) and has been interpreted as pathogenic by Genetic Services Laboratory (University of Chicago), GeneDx, Baylor Genetics, Invitae, Centogene AG - the Rare Disease Company, and OMIM. Of the 5 affected individuals, 1 of those was a homozygote, and 3 were compound heterozygotes that carried reported likely pathogenic variants in trans or with unknown phase, which increases the likelihood that the c.2370_2371delTG variant is pathogenic (PMID: 18799783, 20619503, 29915382; ClinVar ID: 929943). In vitro functional studies provide some evidence that the p.Tyr790Ter variant may slightly impact protein function (PMID: 20886109). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 790 and leads to a premature termination codon at the same position. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated 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_moderate, PM2_supporting, PM3_strong, PS3_supporting (Richards 2015).
OMIM	RCV000006578	SCV000026761	pathogenic	Infantile neuroaxonal dystrophy	2008-10-28	no assertion criteria provided	literature only
OMIM	RCV000006579	SCV000026762	pathogenic	Neurodegeneration with brain iron accumulation 2B	2008-10-28	no assertion criteria provided	literature only