ClinVar Miner

Submissions for variant NM_021971.2(GMPPB):c.1000G>A (rs397509422)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000651273 SCV000773124 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 2018-08-08 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 334 of the GMPPB protein (p.Asp334Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs397509422, ExAC 0.05%). This variant has been reported in the homozygous state in an individual affected myopathy (Invitae) and it has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with congenital muscular dystrophy (PMID: 23768512). It has also been reported in trans with a second, rare GMPPB variant in individuals affected with limb girdle muscular dystrophy with intellectual disability (PMID: 23768512, 26133662). These findings are consistent with autosomal recessive inheritance, and suggest that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 60540). Experimental studies have shown that this missense change disrupts the normal cellular localization of GDP-mannose pyrophorphorylase and leads to a reduction of glycosylated alpha-dystroglycan (PMID: 23768512, 23894383). 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.
Kariminejad - Najmabadi Pathology & Genetics Center RCV000788090 SCV000927088 pathogenic Congenital myasthenic syndrome 2018-12-11 criteria provided, single submitter clinical testing
OMIM RCV000054432 SCV000082909 pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 14 2013-07-11 no assertion criteria provided literature only
OMIM RCV000054433 SCV000082910 pathogenic Muscular dystrophy-dystroglycanopathy (limb-girdle), type c, 14 2013-07-11 no assertion criteria provided literature only

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