ClinVar Miner

Submissions for variant NM_013334.3(GMPPB):c.860G>A (p.Arg287Gln) (rs202160208)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000553832 SCV000894323 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 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000520160 SCV000616733 pathogenic not provided 2017-08-10 criteria provided, single submitter clinical testing The R287Q variant in the GMPPB gene has been reported previously, along with a second variant, in multiple unrelated individuals, the majority of individuals reported have congenital muscular dystrophy, severe intellectual disability, seizures, elevated creatine kinase and/or cerebellar hypoplasia (Carss et al., 2013; Raphael et al., 2014; Cabrera-Serrano et al., 2015). However an individual with R287Q, along with another variant, has also been reported with rhabdomyolysis, onset in adolescents, who also had Rolandic epilepsy, and speech delay (Cabrera-Serrano et al., 2015). The R287Q variant is observed in 23/66172 (0.03%) alleles from individuals of non-Finnish European background, in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). The R287Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. Functional studies in which C2C12 myoblast cell lines were transfected with R287Q showed abnormal subcellular localization of GMPPB, resulting in cytoplasmic protein aggregates, supporting a pathogenic role for R287Q (Carss et al., 2013). A missense variant in the same residue (R287W) has been reported in the Human Gene Mutation Database in association with GMPPB-related disorders (Montagnese et al., 2016; Jensen et al., 2015; Oestergaard et al., 2016), supporting the functional importance of this region of the protein. We interpret R287Q as a pathogenic variant.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000209893 SCV000265550 pathogenic Muscular dystrophy-dystroglycanopathy (limb-girdle), type c, 14 2015-01-13 criteria provided, single submitter research
Invitae RCV000553832 SCV000653760 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 2018-11-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 287 of the GMPPB protein (p.Arg287Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs202160208, ExAC 0.03%). This variant has been reported to segregate with congenital muscular dystrophy-dystroglycanopathy and congenital myasthenic syndrome in multiple families (PMID: 26133662, 24780531). ClinVar contains an entry for this variant (Variation ID: 60545). Experimental studies have shown that this missense change alters protein localization and results in protein aggregation (PMID: 23768512). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Arg287Trp) has been determined to be pathogenic (PMID: 27766311, 27874200, 28478914). This suggests that the arginine residue is critical for GMPPB protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000054439 SCV000082916 pathogenic Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type b, 14 2013-07-11 no assertion criteria provided literature only

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