ClinVar Miner

Submissions for variant NM_013334.3(GMPPB):c.79G>C (p.Asp27His) (rs142336618)

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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 RCV000533184 SCV000894324 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 RCV000444697 SCV000518724 pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing The D27H pathogenic variant in the GMPPB gene has been reported previously in combination with a second GMPPB variant in multiple individuals with proximal muscle weakness generally presenting in the second or third decade (Carss et al., 2013; Jensen et al., 2015; Bharucha-Goebel et al., 2015; Cabrera-Serrano et al., 2015; Belaya et al., 2015; Oestergaard et al., 2016). The NHLBI ESP Exome Sequencing Project reports that D27H was observed in 10/8600 alleles (0.12%) from individuals of European American background, with no homozygous individuals, indicating it may be a rare variant in this population. The D27H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Aspartic acid are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret D27H as a pathogenic variant.
Invitae RCV000533184 SCV000653758 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 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 27 of the GMPPB protein (p.Asp27His). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs142336618, ExAC 0.1%). This variant has been reported in the compound heterozygous state with other GMPPB variants in individuals and families affected with limb-girdle muscular dystrophy, congenital myasthenic syndrome, and in a family affected with muscle weakness along with intellectual disability and epilepsy (PMID: 23768512, 26310427, 26133662, 25770200, 25681410). In the latter family, the variant segregated with disease in three affected individuals (PMID: 25770200). ClinVar contains an entry for this variant (Variation ID: 60546). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000610921 SCV000712246 pathogenic Muscular dystrophy 2017-03-17 criteria provided, single submitter clinical testing The p.Asp27His variant in GMPPB has been reported in the homozygous or compound heterozygous state in at least 15 individuals with muscular dystrophy, and segre gated with disease in 5 affected relatives from 5 families (Carss 2013, Belaya 2 015, Cabrera-Serrano 2015, Jensen 2015, Montagnese 2016, Oestergaard 2016). It w as also identified in 0.1% (89/64040) of European chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142336618). Thi s frequency is low enough that it may be consistent with a recessive carrier fre quency, thoughthere is limited prevalence data for the associated disease. In ad dition, the available evidence suggests that it may be associated with a milder course of disease (Jensen 2015, Montagnese 2016). In summary, this variant meets criteria to be classified as pathogenic for limb-girdle muscular dystrophy in a n autosomal recessive manner.
OMIM RCV000054440 SCV000082917 pathogenic Muscular dystrophy-dystroglycanopathy (limb-girdle), type c, 14 2013-07-11 no assertion criteria provided literature only

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