Submissions for variant NM_003560.4(PLA2G6):c.668C>T (p.Pro223Leu)

dbSNP: rs776753796

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV002275547	SCV002563729	likely pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003096213	SCV003461835	likely pathogenic	Infantile neuroaxonal dystrophy	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 223 of the PLA2G6 protein (p.Pro223Leu). This variant is present in population databases (rs776753796, gnomAD 0.006%). This missense change has been observed in individuals with PLA2G6-related conditions (PMID: 29454663, 31493945, 36790591). ClinVar contains an entry for this variant (Variation ID: 1701439). 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 with a positive predictive value of 80%. This variant disrupts the p.Pro223 amino acid residue in PLA2G6. Other variant(s) that disrupt this residue have been observed in individuals with PLA2G6-related conditions (PMID: 18799783, 29454663, 31493945), which suggests that this may be a clinically significant amino acid residue. 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003096214	SCV003761022	uncertain significance	PLA2G6-associated neurodegeneration	2023-01-24	criteria provided, single submitter	curation	The p.Pro223Leu variant in PLA2G6 has been reported in 2 individuals with PLA2G6-associated neurodegeneration (PMID: 29454663, 31493945) and has been identified in 0.005% (1/18382) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs776753796). 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 compound heterozygotes that carried variants of uncertain significance in trans, which increases the likelihood that the p.Pro223Leu variant is pathogenic (PMID: 29454663, 31493945). 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.Pro223Leu variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PM3_supporting (Richards 2015).
Neuberg Centre For Genomic Medicine, NCGM	RCV003339949	SCV004048238	uncertain significance	Neurodegeneration with brain iron accumulation 2B		criteria provided, single submitter	clinical testing	The missense variant c.668C>T (p.Pro223Leu) in PLA2G6 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Pro223Leu variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0003981% is reported in gnomAD. The amino acid Pro at position 223 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Pro223Leu in PLA2G6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates.For these reasons, this variant has been classified as Uncertain Significance
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003403769	SCV004122258	likely pathogenic	Neurodegeneration with brain iron accumulation	2023-10-27	criteria provided, single submitter	clinical testing	Variant summary: PLA2G6 c.668C>T (p.Pro223Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251208 control chromosomes. c.668C>T has been reported in the literature in at-least three individuals affected with features of Neurodegeneration With Brain Iron Accumulation (examples, Arslan_2020, Chen_2018, Sait_2023). Particularly, the variant was reported at a compound heterozygous state along with a pathogenic nonsense variant of PLA2G6 in an individual with PLA2G6-associated neurodegeneration through Exome sequencing (Sait_2023). These data indicate that the variant may 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: 31493945, 29454663, 36790591). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=2; likely pathogenic, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.