ClinVar Miner

Submissions for variant NM_021971.2(GMPPB):c.953T>C (p.Val318Ala)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000691392 SCV000819168 uncertain significance 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 2018-04-26 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 318 of the GMPPB protein (p.Val318Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs559784211, ExAC 0.02%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with muscle weakness, exercise intolerance and elevated CPK level (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. In addition, this variant has been reported in combination with another GMPPB variant in an individual affected with limb-girdle muscular dystrophy with intellectual disability (PMID: 26310427). This variant is also known as c.1043T>C, p.Val345Ala in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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