ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.430T>C (p.Phe144Leu) (rs150719105)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000596795 SCV000800756 likely pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2017-04-18 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000414479 SCV000700607 likely pathogenic not provided 2017-04-28 criteria provided, single submitter clinical testing
GeneDx RCV000414479 SCV000490727 likely pathogenic not provided 2016-11-18 criteria provided, single submitter clinical testing The F144L variant has previously been reported in unrelated individuals with congenital disorder of glycosylation type 1a (CDG-1a) who were heterozygous for F144L and another missense variant in the PMM2 gene, although the phase of these variants was not reported (Kondo et al., 1999; Kane et al., 2016). The 1000 Genomes Project Consortium reports F144L was observed in 2/1008 alleles from individuals of East Asian background. The F144L 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 conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (E139K, R141H, D148N) have been reported in the Human Gene Mutation Database in association with CDG-1a (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000596795 SCV000965006 likely pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 144 of the PMM2 protein (p.Phe144Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs150719105, ExAC 0.7%). This variant has been observed to segregate with carbohydrate-deficient glycoprotein syndrome type 1 in several families (PMID: 10066032) and in an individual affected with this condition (PMID: 28122681). Isoelectric focusing (IEF) analysis of serum proteins revealed a pattern consistent with CDG1 (PMID: 10066032). ClinVar contains an entry for this variant (Variation ID: 197658). 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 C15"). 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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