ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.109C>T (p.Gln37Ter) (rs764353860)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000780611 SCV000918027 likely pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-09-24 criteria provided, single submitter clinical testing Variant summary: PMM2 c.109C>T (p.Gln37X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., p.Arg194X). The variant allele was found at a frequency of 0.00014 in 244386 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PMM2 causing Congenital Disorder of Glycosylation Type 1a (0.00014 vs 0.0056), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.109C>T in individuals affected with Congenital Disorder of Glycosylation Type 1a and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000780611 SCV000963575 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-10-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln37*) in the PMM2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs764353860, ExAC 0.1%). This variant has not been reported in the literature in individuals with PMM2-related disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in PMM2 are known to be pathogenic (PMID: 19862844). For these reasons, this variant has been classified as Pathogenic.

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