Submissions for variant NM_003560.4(PLA2G6):c.1754C>T (p.Thr585Ile)

gnomAD frequency: 0.00001  dbSNP: rs587784338

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147302	SCV000194675	pathogenic	Iron accumulation in brain	2013-02-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700467	SCV005204218	uncertain significance	not specified	2024-06-20	criteria provided, single submitter	clinical testing	Variant summary: PLA2G6 c.1754C>T (p.Thr585Ile) 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 was absent in 251170 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1754C>T has been reported in the literature in at least one compound heterozygous individual affected with Infantile Neuroaxonal Dystrophy (Morgan_2006). These report(s) do not provide unequivocal conclusions about association of the variant with Infantile Neuroaxonal Dystrophy. 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: 18799783, 16783378). ClinVar contains an entry for this variant (Variation ID: 159747). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005089714	SCV005842187	likely pathogenic	Infantile neuroaxonal dystrophy	2024-04-12	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 585 of the PLA2G6 protein (p.Thr585Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical feature of PLA2G6-related conditions (PMID: 16783378; Invitae). 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: 159747). 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%. 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.