Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000690678 | SCV000818377 | likely pathogenic | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14; Autosomal recessive limb-girdle muscular dystrophy type 2T | 2024-01-08 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 319 of the GMPPB protein (p.Arg319Cys). This variant is present in population databases (rs780867515, gnomAD 0.007%). This missense change has been observed in individual(s) with Congenital myasthenic syndrome and/or congenital myasthenic syndrome (PMID: 33756069; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Arg346Cys. ClinVar contains an entry for this variant (Variation ID: 569923). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GMPPB protein function with a positive predictive value of 80%. This variant disrupts the Arg346 amino acid residue in GMPPB. Other variant(s) that disrupt this residue have been observed in individuals with GMPPB-related conditions (PMID: 25681410), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |