ClinVar Miner

Submissions for variant NM_021971.2(GMPPB):c.859C>T (p.Arg287Trp) (rs142908436)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000698947 SCV000827638 pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 14; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type b, 14; Muscular dystrophy-dystroglycanopathy (limb-girdle), type c, 14 2018-06-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 287 of the GMPPB protein (p.Arg287Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs142908436, ExAC 0.03%). This variant has been observed in combination with other GMPPB variants in individuals affected with GMPPB-related disease (PMID: 26133662, 27766311, 27874200, 28478914). ClinVar contains an entry for this variant (Variation ID: 225925). Experimental studies have shown that this missense change severely impacts the expression of the GMPPB protein in vitro (PMID: 26133662). A variant that disrupts the p.Arg287 amino acid residue in GMPPB has been observed in affected individuals (PMID: 24780531, 26133662). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000609930 SCV000712240 likely pathogenic Muscular dystrophy 2017-03-17 criteria provided, single submitter clinical testing The p.Arg287Trp variant in GMPPB has been reported in the compound heterozygous state in 5 individuals with muscular dystrophy (Belaya 2015, Jensen 2015, Oester gaard 2016, Montagnese 2016), 4 of whom carried the same pathogenic variant (p.A sp27His) on the other allele. It segregated with disease in 1 affected family me mber (Oestergaard 2016). The p.Arg287Trp variant has also been identified in 21/ 66178 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs142908436). Computational prediction tools and con servation analysis do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that the p.Arg287Trp variant may impact protein stability (Belaya 2015); however, these types of ass ays may not accurately represent biological function. Finally, another variant a t the same position (p.Arg287Gln) has been reported in multiple individuals with muscular dystrophy. In summary, although additional studies are needed to fully establish its clinical significance, the p.Arg287Trp variant is likely pathogen ic.
OMIM RCV000211126 SCV000268097 pathogenic Muscular dystrophy-dystroglycanopathy (limb-girdle), type c, 14 2018-09-25 no assertion criteria provided literature only

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