ClinVar Genomic variation as it relates to human health

Variant summary: PLA2G6 c.1634A>G (p.Lys545Arg) results in a conservative amino acid change located in the patatin-like phospholipase domain (IPR002641) of 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 2.4e-05 in 251320 control chromosomes (gnomAD). c.1634A>G has been reported in the literature as a compound heterozygous genotype in multiple well-genotyped individuals affected with PLA2G6-associated neurodegeneration with or without brain iron accumulation, including one case of de novo inheritance and multiple instances where it was in trans with a pathogenic variant (e.g. Guo_2017, de Souza_2017, Koh_2019, Kim_2019). 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. However, another variant affecting the same amino acid (p.Lys545Thr) has been observed in affected individuals in the HGMD database, suggesting Lys545 may be important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 27395053, 31104286, 30302010, 28716262). One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 545 of the PLA2G6 protein (p.Lys545Arg). This variant is present in population databases (rs121908681, gnomAD 0.03%). This missense change has been observed in individual(s) with PLA2G6-related conditions (PMID: 27395053, 30302010, 31104286). 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: 159741). 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%. This variant disrupts the p.Lys545 amino acid residue in PLA2G6. Other variant(s) that disrupt this residue have been observed in individuals with PLA2G6-related conditions (PMID: 16783378, 19138334), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

The p.Lys545Arg variant in PLA2G6 has been reported in 4 individuals with PLA2G6-associated neurodegeneration (PMID: 30302010, 27395053, 33835755, 28716262), and has been identified in 0.03% (6/18394) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121908681). 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. Of the 4 affected individuals, 2 were compound heterozygotes that carried reported likely pathogenic variants in trans, which increases the likelihood that the p.Lys545Arg variant is pathogenic (Variant ID: 279875; PMID: 30302010, 27395053). This variant was found to be de novo in 1 individual with confirmed paternity and maternity (PMID: 27395053). This variant has also been reported in ClinVar (Variation ID#: 159741) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Lys545Thr, has been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 16783378, 32581362; ClinVar ID: 6196). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PP3, PS2_moderate, PM3_strong, PM5 (Richards 2015).