ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.24del (p.Cys9fs) (rs768021123)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169057 SCV000220219 likely pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2014-04-04 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America RCV000169057 SCV000920017 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-07-27 criteria provided, single submitter clinical testing Variant summary: PMM2 c.24delC (p.Cys9AlafsX27) 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. The variant allele was found at a frequency of 1.7e-05 in 236838 control chromosomes. c.24delC has been reported in the literature in individuals affected with Congenital Disorder of Glycosylation Type 1a (Arnoux_2008, Le Bizec_2005, Schollen_2002, Westphal_2001). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, which showed the variant to have <10% enzyme activity in a yeast expression system (Westphal_2001). 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 pathogenic.
Invitae RCV000169057 SCV000832586 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-03-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys9Alafs*27) in the PMM2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs768021123, ExAC 0.004%). This variant has been reported in individuals affected with congenital disorder of glycosylation (PMID: 11058895, 12297897, 18093857, 19168813). ClinVar contains an entry for this variant (Variation ID: 188744). 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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