Submissions for variant NM_003560.4(PLA2G6):c.1427+1G>A

gnomAD frequency: 0.00001  dbSNP: rs750939090

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000500147	SCV000588379	likely pathogenic	Infantile neuroaxonal dystrophy	2017-06-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763483	SCV000894266	likely pathogenic	Infantile neuroaxonal dystrophy; Neurodegeneration with brain iron accumulation 2B; Autosomal recessive Parkinson disease 14	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000500147	SCV001163449	pathogenic	Infantile neuroaxonal dystrophy		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001783002	SCV002018849	pathogenic	not provided	2021-04-06	criteria provided, single submitter	clinical testing
Invitae	RCV000500147	SCV002242836	pathogenic	Infantile neuroaxonal dystrophy	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 10 of the PLA2G6 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PLA2G6 are known to be pathogenic (PMID: 16783378, 18570303, 18799783, 22213678). This variant is present in population databases (rs750939090, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with infantile neuroaxonal dystrophy and early onset Parkinson's disease (PMID: 19138334, 31496990). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 437465). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002527311	SCV003760999	pathogenic	PLA2G6-associated neurodegeneration	2023-01-24	criteria provided, single submitter	curation	The c.1427+1G>A variant in PLA2G6 has been reported in 5 individuals with PLA2G6-associated neurodegeneration (PMID: 19138334, 31496990, 34630504) and has been identified in 0.01% (2/18388) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs750939090). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 437465) and has been interpreted as pathogenic or likely pathogenic by Genomic Research Center (Shahid Beheshti University of Medical Sciences), Fulgent Genetics, Baylor Genetics, Invitae, and PerkinElmer Genomics. Of the 5 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the c.1427+1G>A variant is pathogenic (VariationID: 30371; PMID: 31496990). This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the PLA2G6 gene is an established disease mechanism in autosomal recessive PLA2G6-associated neurodegeneration. The phenotype of an individual compound heterozygous for this variant is highly specific for PLA2G6-associated neurodegeneration based on brain iron accumulation on MRI consistent with disease (PMID: 31496990). 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, PM3, PP4 (Richards 2015).