ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.323C>T (p.Ala108Val) (rs200503569)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078587 SCV000230062 likely pathogenic not provided 2013-08-30 criteria provided, single submitter clinical testing
GeneDx RCV000078587 SCV000617239 pathogenic not provided 2017-07-05 criteria provided, single submitter clinical testing The A108V variant in the PMM2 gene has been reported previously in the compound heterozygous state in multiple unrelated individuals with CDG-1a (Matthijs et al., 1997; Le Bizec et al., 2005; Monin et al., 2014; Barone et al., 2015). The A108V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A108V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret A108V as a pathogenic variant.
Counsyl RCV000178072 SCV000797229 likely pathogenic Congenital disorder of glycosylation, type Ia 2018-01-22 criteria provided, single submitter clinical testing
Invitae RCV000178072 SCV000938657 likely pathogenic Congenital disorder of glycosylation, type Ia 2018-11-02 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 108 of the PMM2 protein (p.Ala108Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs200503569, ExAC 0.003%). This variant has been observed in several individuals affected with PMM2-related conditions (PMID: 9140401, 25355454, Invitae). ClinVar contains an entry for this variant (Variation ID: 92800). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.

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