ClinVar Genomic variation as it relates to human health

A published R104Q variant that is likely pathogenic has been identified in the PRICKLE1 gene. The R104Q variant has been previously reported as a homozygous variant in multiple unrelated individuals with progressive myoclonus epilepsy (PME)-ataxia syndrome; individuals in these families who were heterozygous for the variant were not affected (Bassuk et al., 2008). Functional studies suggest that the R104Q variant impairs protein function (Bassuk et al., 2008). The R104Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R104Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

A Heterozygous Missense variant c.311G>A in Exon 4 of the PRICKLE1 gene that results in the amino acid substitution p.Arg104Gln was identified. The observed variant has a maximum allele frequency of 0.00001/0.00006% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as LikelyPathogenic. The p. Arg104Gln missense variant in PRICKLE1 has been previously reported in the homozygous in at least 3 unrelated families with progressive myoclonus epilepsy-ataxia (PME) syndrome. Functional studies suggest that this variant disrupts protein function and subcellular localization (Bassuk AG et al., 2008). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

Variant summary: PRICKLE1 c.311G>A (p.Arg104Gln) results in a conservative amino acid change located in the PET domain (IPR010442) 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 1.2e-05 in 251416 control chromosomes. c.311G>A has been reported in the literature in multiple individuals affected with Epilepsy, progressive myoclonic, 1B (Bassuk_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function suggesting it impacts protein function (Bassuk_2008). The following publications have been ascertained in the context of this evaluation (PMID: 18976727, 32214227, 35040250). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PRICKLE1 function (PMID: 18976727). 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 PRICKLE1 protein function. ClinVar contains an entry for this variant (Variation ID: 2283). This missense change has been observed in individuals with progressive myoclonic epilepsy (PMID: 18976727, 32214227). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs113994140, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 104 of the PRICKLE1 protein (p.Arg104Gln).

PS3, PM2, PM3, PP1