Submissions for variant NM_003560.4(PLA2G6):c.386T>C (p.Leu129Pro)

gnomAD frequency: 0.00019  dbSNP: rs374746113

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147324	SCV000194697	uncertain significance	Iron accumulation in brain	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000414098	SCV000490724	likely pathogenic	not provided	2024-06-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26633542, 29395073, 29859652, 35247231, 35152491, 34307755)
Ambry Genetics	RCV000623680	SCV000742160	likely pathogenic	Inborn genetic diseases	2021-09-01	criteria provided, single submitter	clinical testing	The c.386T>C (p.L129P) alteration is located in exon 3 (coding exon 2) of the PLA2G6 gene. This alteration results from a T to C substitution at nucleotide position 386, causing the leucine (L) at amino acid position 129 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.01% (14/278142) total alleles studied. The highest observed frequency was 0.06% (14/24504) of African alleles. The p.L129P alteration has detected in the homozygous state and in trans with other PLA2G6 alterations in patients with features consistent with neurodegeneration with brain iron accumulation (Drecourt, 2018; Gitiaux, 2018; Ambry internal data). This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
Illumina Laboratory Services, Illumina	RCV001270755	SCV001451505	uncertain significance	Infantile neuroaxonal dystrophy	2019-02-14	criteria provided, single submitter	clinical testing	The PLA2G6 c.386T>C (p.Leu129Pro) variant is a missense variant that has been reported in one study, in which it is found in one presumably compound heterozygous individual with a second missense variant (Gitiaux et al. 2018). Control data are unavailable for this variant, which is reported at a frequency of 0.000571 in the African/African-American population of the Genome Aggregation Database. Based on the limited evidence, the p.Leu129Pro variant is classified as a variant of uncertain significance for infantile neuroaxonal dystrophy 1.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001270755	SCV001531720	likely pathogenic	Infantile neuroaxonal dystrophy	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 129 of the PLA2G6 protein (p.Leu129Pro). This variant is present in population databases (rs374746113, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of PLA2G6-related conditions (PMID: 29395073, 34307755, 35247231). 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: 159768). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PLA2G6 protein function with a negative predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700468	SCV001748826	likely pathogenic	Neurodegeneration with brain iron accumulation	2024-06-20	criteria provided, single submitter	clinical testing	Variant summary: PLA2G6 c.386T>C (p.Leu129Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 391476 control chromosomes, predominantly at a frequency of 0.00066 within the African or African-American subpopulation in the gnomAD database (v2.1 and v3.1). This frequency is somewhat lower than the maximum expected for a pathogenic variant in PLA2G6 causing Neurodegeneration with Brain Iron Accumulation (0.00085), allowing no conclusion about variant significance. The variant, c.386T>C, has been reported in the literature in compound heterozygous individuals affected with Neurodegeneration with Brain Iron Accumulation, infantile neuroaxonal dystrophy, or early-onset Parkinsonism with iron accumulation in the brain (e.g. Drecourt_2018, Gitiaux_2018, deOliveira_2021, Borja_2022) or in a patient with unspecified nervous system phenotype, where no variant in trans was specified (e.g. Retterer_2015). At least one publication reports experimental evidence evaluating an impact on protein function demonstrating iron overload and TfR1 dysregulation in patient derived fibroblasts (e.g. Drecourt_2018). The following publications have been ascertained in the context of this evaluation (PMID: 26633542, 29395073, 29859652, 34307755, 35247231). ClinVar contains an entry for this variant (Variation ID: 159768). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002515981	SCV003761024	uncertain significance	PLA2G6-associated neurodegeneration	2023-01-24	criteria provided, single submitter	curation	The p.Leu129Pro variant in PLA2G6 has been reported in 3 individuals with PLA2G6-associated neurodegeneration (PMID: 29859652, 34307755, 35247231) and has been identified in 0.06% (14/24504) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs374746113). 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#: 159768) and has been interpreted as likely pathogenic by GeneDx and Ambry Genetics and as a variant of uncertain significance by Illumina Laboratory Services (Illumina), Invitae, Genetic Services Laboratory (University of Chicago), and Women's Health and Genetics/Laboratory Corporation of America (LabCorp). Of the 3 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, which increases the likelihood that the p.Leu129Pro variant is pathogenic (PMID: 35247231). In vitro functional studies provide some evidence that the p.Leu129Pro variant may slightly impact protein function (PMID: 29395073). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Leu129Pro variant is uncertain. ACMG/AMP Criteria applied: PS3_moderate, PM3 (Richards 2015).
Undiagnosed Diseases Network, NIH	RCV001270755	SCV003915648	likely pathogenic	Infantile neuroaxonal dystrophy	2022-04-01	no assertion criteria provided	clinical testing