ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs768021123
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169057 SCV000220219 likely pathogenic PMM2-congenital disorder of glycosylation 2014-04-04 criteria provided, single submitter literature only
Labcorp Genetics (formerly Invitae), Labcorp RCV000169057 SCV000832586 pathogenic PMM2-congenital disorder of glycosylation 2024-01-25 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. Loss-of-function variants in PMM2 are known to be pathogenic (PMID: 19862844). This variant is present in population databases (rs768021123, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with congenital disorder of glycosylation (PMID: 11058895, 12297897, 18093857, 19168813). ClinVar contains an entry for this variant (Variation ID: 188744). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169057 SCV000920017 pathogenic PMM2-congenital disorder of glycosylation 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.
CeGaT Center for Human Genetics Tuebingen RCV001091537 SCV001247653 pathogenic not provided 2022-06-01 criteria provided, single submitter clinical testing PMM2: PM3:Strong, PVS1:Strong, PM2
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001091537 SCV002009269 pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000169057 SCV002795486 pathogenic PMM2-congenital disorder of glycosylation 2022-01-26 criteria provided, single submitter clinical testing
GeneDx RCV001091537 SCV004030644 pathogenic not provided 2023-08-11 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect of reduction of PMM activity to negative control level (PMID: 11715002); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12297897, 12529711, 11058895, 18093857, 33643843, 19168813, 11715002, 15844218)
PreventionGenetics, part of Exact Sciences RCV003422060 SCV004117937 pathogenic PMM2-related disorder 2022-10-27 criteria provided, single submitter clinical testing The PMM2 c.24delC variant is predicted to result in a frameshift and premature protein termination (p.Cys9Alafs*27). This variant has been reported in individuals with autosomal recessive congenital disorder of glycosylation 1a (Matthijs et al. 2000. PubMed ID: 11058895; Jamroz et al. 2009. PubMed ID: 19168813; Westphal et al. 2001. PubMed ID: 11715002). This variant is reported in 0.0037% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-8891762-TC-T). Frameshift variants in PMM2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics RCV000169057 SCV004205260 pathogenic PMM2-congenital disorder of glycosylation 2024-02-21 criteria provided, single submitter clinical testing
Natera, Inc. RCV000169057 SCV001457162 pathogenic PMM2-congenital disorder of glycosylation 2020-09-16 no assertion criteria provided clinical testing

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