ClinVar Genomic variation as it relates to human health

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.87). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000648403). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 29096607). A different missense change at the same codon (p.Arg95Trp) has been reported to be associated with PIGN related disorder (PMID: 26633542). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Variant summary: PIGN c.284G>A (p.Arg95Gln) results in a conservative amino acid change located in the GPI ethanolamine phosphate transferase 1, N-terminal domain (IPR037671) 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 1.6e-05 in 246758 control chromosomes. c.284G>A has been reported in the literature as a biallelic homozygous or compound heterozygous genotype in individuals affected with features of Multiple Congenital Anomalies-Hypotonia Syndrome 1 such as hypotonia, global developmental delay, and focal epilepsy, severe hypotonia and muscular dystrophy (example, Thiffault_2017, Jalkh_2019, Duval_2021). 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 95 of the PIGN protein (p.Arg95Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with PIGN-related conditions (PMID: 29096607, 33763700; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 648403). 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 PIGN protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

Reported in an individual with global developmental delay, intractable epilepsy, severe hypotonia, and muscular atrophy, however, it is unclear whether a second PIGN variant was present (PMID: 33763700); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29096607, 33763700)