Submissions for variant NM_021971.4(GMPPB):c.862C>T (p.Arg288Trp)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002604254	SCV002952776	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	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 288 of the GMPPB protein (p.Arg288Trp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of muscular dystrophy-dystroglycanopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 1920781). 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 p.Arg288 amino acid residue in GMPPB. Other variant(s) that disrupt this residue have been observed in individuals with GMPPB-related conditions (PMID: 30257713), 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.
Revvity Omics, Revvity	RCV003134458	SCV003816951	uncertain significance	not provided	2021-08-05	criteria provided, single submitter	clinical testing