Submissions for variant NM_003560.4(PLA2G6):c.1982C>T (p.Thr661Met)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003508541	SCV004281220	pathogenic	Infantile neuroaxonal dystrophy	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 661 of the PLA2G6 protein (p.Thr661Met). This variant is present in population databases (rs767689496, gnomAD 0.006%). This missense change has been observed in individual(s) with infantile neuroaxonal dystrophy (PMID: 23749988, 31069529, 32005694, 35032046). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003508541	SCV005077195	pathogenic	Infantile neuroaxonal dystrophy	2024-04-19	criteria provided, single submitter	clinical testing	Variant summary: PLA2G6 c.1982C>T (p.Thr661Met) results in a non-conservative amino acid change located in the Patatin-like phospholipase domain (IPR002641) of 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 8e-06 in 249664 control chromosomes. c.1982C>T has been reported in the literature in multiple individuals affected with Infantile Neuroaxonal Dystrophy, Neurodegeneration with brain iron accumulation and related disorders (Sukenik-Halevy_2022, Koroglu_2012, Arslan_2020, Dong_2020, Ganapathy_2019, Sait_2023). These data indicate that the variant is very 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: 31493945, 32005694, 31069529, 23749988, 36790591, 35032046). ClinVar contains an entry for this variant (Variation ID: 2724426). Based on the evidence outlined above, the variant was classified as pathogenic.