ClinVar

Description

The heterozygous p.Arg1311His variant in TOGARAM1 was identified by our study, in the compound heterozygous state with a variant of uncertain significance (dbSNP ID: rs200833388), in monozygotic twins with Brown syndrome, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). These individuals also carried a variant of uncertain significance (dbSNP ID: rs200833388), however the phase of these variants are unknown at this time. We believe this is a possible phenotype expansion for TOGARAM1-related disorders. The p.Arg1311His variant in TOGARAM1 has not been previously reported in individuals with Joubert syndrome 37 but has been identified in 0.003% (1/30716) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs201399500). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg1311Cys, 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: 32453716, Variation ID: 979054). 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, the clinical significance of the p.Arg1311His variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM5_Supporting, PP3 (Richards 2015).