ClinVar Miner

Submissions for variant NM_021971.4(GMPPB):c.781C>T (p.Arg261Cys)

gnomAD frequency: 0.00001  dbSNP: rs746357591
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001054940 SCV001219299 uncertain significance 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 2022-07-05 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 261 of the GMPPB protein (p.Arg261Cys). This variant is present in population databases (rs746357591, gnomAD 0.004%). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 26133662). ClinVar contains an entry for this variant (Variation ID: 850712). 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 not expected to disrupt GMPPB protein function. Experimental studies have shown that this missense change affects GMPPB function (PMID: 31211170). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV003106106 SCV003761838 likely pathogenic not provided 2022-07-27 criteria provided, single submitter clinical testing Published functional studies suggest a damaging effect (partial decrease of enzymatic activity with no demonstrated phenotypic effect on the animal model) (Liu et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31211170, 26133662, 35006422)
Revvity Omics, Revvity RCV003106106 SCV003816952 uncertain significance not provided 2024-01-02 criteria provided, single submitter clinical testing

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