ClinVar

Description

The p.Arg129Trp variant in POMGNT1 has been reported in at least five individuals with POMGNT1-associated muscular dystrophy-dystroglycanopathy (PMID: 28688748, PMID: 30961548, PMID: 34324503, ClinVar SCV002029242.2), and has been identified in 0.002% (2/113568) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs375431575). 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. This variant has also been reported in ClinVar (Variation ID #558512) and has been interpreted as pathogenic by Invitae and CeGaT Center for Human Genetics Tuebingen, as likely pathogenic by Molecular Genetics (Royal Melbourne Hospital), Cytogenetics and Genomics Lab (Cyprus Institute Of Neurology and Genetics), and Myriad Women's Health, Inc., and as of uncertain significance by Counsyl, Illumina, and Natera, Inc. Of the five affected individuals, two were compound heterozygotes who carried a reported pathogenic or likely pathogenic variant in trans, which increases the likelihood that the p.Arg129Trp variant is pathogenic (PMID: 30961548, PMID: 34324503; ClinvarID: 56582, 984973). 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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for POMGNT1-associated muscular dystrophy-dystroglycanopathy. ACMG/AMP Criteria applied: PM3_Strong, PM2_supporting, PP3 (Richards 2015).