Submissions for variant NM_003560.4(PLA2G6):c.680C>T (p.Ala227Val)

gnomAD frequency: 0.00002  dbSNP: rs764957976

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002016608	SCV002306354	uncertain significance	Infantile neuroaxonal dystrophy	2022-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 227 of the PLA2G6 protein (p.Ala227Val). This variant is present in population databases (rs764957976, gnomAD 0.003%). This missense change has been observed in individuals with PLA2G6-related conditions (PMID: 28150298, 30340910; Invitae). ClinVar contains an entry for this variant (Variation ID: 1511286). 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 expected to disrupt PLA2G6 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002545570	SCV003761021	uncertain significance	PLA2G6-associated neurodegeneration	2023-01-24	criteria provided, single submitter	curation	The p.Ala227Val variant in PLA2G6 has been reported in 2 individuals with PLA2G6-associated neurodegeneration (PMID: 28150298, 29577258) and has been identified in 0.003% (1/34586) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs764957976). 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. Of the 2 affected individuals, both were homozygotes, which increases the likelihood that the p.Ala227Val variant is pathogenic (PMID: 28150298, 29577258). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ala227Val variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PP3, PM3 (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003402056	SCV004122259	likely pathogenic	Neurodegeneration with brain iron accumulation	2023-10-27	criteria provided, single submitter	clinical testing	Variant summary: PLA2G6 c.680C>T (p.Ala227Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251178 control chromosomes. c.680C>T has been reported in the literature in at-least two twins diagnosed with PLA2G6-related neurodegeneration (example, Tello_2017, Darling_2019). Both copies of the variant were inherited from the father by uniparental disomy. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30340910, 28150298). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.