ClinVar Miner

Submissions for variant NM_013334.3(GMPPB):c.1069G>A (p.Val357Ile) (rs199922550)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623470 SCV000741092 uncertain significance Inborn genetic diseases 2015-11-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
GeneDx RCV000440664 SCV000521337 likely pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing The V357I (aka V330I) variant in the GMPPB gene has been reported previously in multiple unrelated individuals with limb girdle muscular dystrophy who also harbored another GMPPB variant (Carss et al., 2013; Jensen et al., 2015). The V357I variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V357I variant is associated with mislocalization and aggregation of the protein when transfected into myoblasts (Carss et al., 2013). The V357I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, but this substitution occurs at a position that is conserved across species. The V357I variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Genetic Services Laboratory, University of Chicago RCV000501778 SCV000595010 likely pathogenic Muscular dystrophy-dystroglycanopathy 2016-07-18 criteria provided, single submitter clinical testing
Invitae RCV000651278 SCV000773129 likely 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 2018-04-16 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 330 of the GMPPB protein (p.Val330Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs199922550, ExAC 0.01%). This variant has been reported in combination with another GMPPB variant in individuals affected with limb-girdle muscular dystrophy (PMID: 23768512, 27766311, 26310427). This variant is also known as c.1069G>A (p.Val357Ile) in the literature. Experimental studies have shown that this missense change results in a GMPPB protein that forms cytoplasmic aggregates in cultured myoblasts (PMID: 23768512). 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.
OMIM RCV000054441 SCV000082918 pathogenic Muscular dystrophy-dystroglycanopathy (limb-girdle), type c, 14 2013-07-11 no assertion criteria provided literature only

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