ClinVar

Description

The heterozygous p.Arg269His variant in TRPV4 was identified by our study in one individual whose features included congenital fibrosis of the extraocular muscles of the right eye, abducens palsy of the left eye, motor axonal neuropathy, and arthrogryposis, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). Trio genome analysis showed this variant to be de novo. We believe this is a possible phenotype expansion for TRPV4-related disease The p.Arg269His variant in TRPV4 has been previously reported in over 10 unrelated individuals with autosomal dominant TRPV4-related disease (PMID: 20037586, PMID: 27751652, PMID: 26948711, PMID: 30230566, PMID: 20037588, PMID: 20037587, PMID: 20460441, PMID: 24575025, PMID: 24789864) and segregated with disease in 59 affected relatives from 7 families (PMID: 20037586, PMID: 26948711, PMID: 30230566, PMID: 20037588, PMID: 20037587, PMID: 20460441, PMID: 24575025). 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 at least two unrelated individuals with confirmed maternity and paternity (PMID: 24789864, PMID: 30230566). This variant has also been reported in ClinVar (Variation ID: 5000) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg269His variant may impact protein function (PMID: 21454511, PMID: 21288981, PMID: 20037588, PMID: 20037586). However, these types of assays may not accurately represent biological function. 2 additional pathogenic or likely pathogenic variants, resulting in a different amino acid change at the same position, p.Arg269Ser and p.Arg269Cys, have 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: 20037586, 21336783, 24789864, 25900305, 26110311; Variation ID: 536867, 5002). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein.In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant TRPV4-related disease. ACMG/AMP Criteria applied: PS2_Moderate, PS3, PS4, PM2_Supporting, PM5_Supporting, PP1_strong (Richards 2015).