ClinVar

Description

The hemizygous p.Asn179Ser variant in ATRX was identified by our study in 3 siblings with x-linked mental retardation-hypotonic facies syndrome. This variant is assumed de novo in 1 individual, but maternity and paternity have not been confirmed (PMID: 16813605). The variant has been reported in at least 5 individuals of Japanese and unknown ethnicity with x-linked mental retardation-hypotonic facies syndrome (PMID: 16813605, 10995512, 8968741, 25252072, 33229608), but was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 93141) as pathogenic by GeneDx, HudsonAlpha Institute for Biotechnology, and EGL Genetic Diagnostics, Eurofins Clinical Diagnostics. In vitro functional studies provide some evidence that the p.Asn179Ser variant may slightly impact protein function (PMID: 8968741). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in ATRX 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. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM6, PP2, PP3, PS4_supporting, PS3_supporting (Richards 2015).