Submissions for variant NM_000303.3(PMM2):c.97C>T (p.Gln33Ter)

gnomAD frequency: 0.00001  dbSNP: rs149530060

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000989519	SCV001139934	pathogenic	PMM2-congenital disorder of glycosylation	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000989519	SCV001587982	pathogenic	PMM2-congenital disorder of glycosylation	2023-10-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln33*) 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 (rs149530060, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with PMM2-congenital disorder of glycosylation (PMID: 28139241). ClinVar contains an entry for this variant (Variation ID: 803211). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000989519	SCV002794503	likely pathogenic	PMM2-congenital disorder of glycosylation	2022-02-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000989519	SCV004039146	pathogenic	PMM2-congenital disorder of glycosylation	2023-08-02	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.97C>T (p.Gln33X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant allele was found at a frequency of 1.2e-05 in 248656 control chromosomes (gnomAD). c.97C>T has been reported in the literature in at least one individual affected with Congenital Disorder Of Glycosylation Type 1a (e.g. Perez-Cerda_2017). These data indicate that the variant is likely associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 28139241). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV003332275	SCV004039669	pathogenic	not provided	2023-09-27	criteria provided, single submitter	clinical testing	Nonsense 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: 26014514, 28139241, 35279850)
Baylor Genetics	RCV000989519	SCV004204832	pathogenic	PMM2-congenital disorder of glycosylation	2024-03-12	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000989519	SCV002089466	pathogenic	PMM2-congenital disorder of glycosylation	2020-03-22	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003936246	SCV004756645	pathogenic	PMM2-related disorder	2024-02-23	no assertion criteria provided	clinical testing	The PMM2 c.97C>T variant is predicted to result in premature protein termination (p.Gln33*). This variant was reported in individuals with congenital disorder of glycosylation (see, for example, Pérez-Cerdá et al. 2017. PubMed ID: 28139241). This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/). Nonsense variants in PMM2 are expected to be pathogenic. This variant is interpreted as pathogenic.