ClinVar

Description

The heterozygous p.Arg2799His variant in PIEZO2 was identified by our study in one individual with features including Duane retraction syndrome, congenital ptosis, and vertical gaze abnormalities, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). The p.Arg2799His variant in PIEZO2 has been previously reported in 16 unrelated individuals with PIEZO2-related disorders (PMID: 3658875, PMID: 31680123, PMID: 24726473, PMID: 32901917, PMID: 27714920, PMID: 34958143, PMID: 33060286) and segregated with disease in 13 affected relatives from 5 families (PMID: 36588752, PMID: 24726473, PMID: 27714920). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 5 individuals with confirmed paternity and maternity (PMID: 24726473, PMID: 32901917, PMID: 34958143). This variant has also been reported in ClinVar (Variation ID: 137629) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. The number of missense variants reported in PIEZO2 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. Multiple variants in the same region as the p.Arg2799His variant have been reported in association with disease in ClinVar and in the literature, suggesting that this variant is in a hot spot and slightly supports pathogenicity (PMID: 24726473; ClinVar Variation ID: 631524, 137631, 137632, 137634). One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg2686Cys, has been reported in association with disease in the literature and in ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 24726473, Variation ID: 137630). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant PIEZO2-related disorders. ACMG/AMP Criteria applied: PS2_VeryStrong, PS4, PM1_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP2, PP3 (Richards 2015).