Submissions for variant NM_000303.3(PMM2):c.53C>G (p.Thr18Ser)

gnomAD frequency: 0.00001  dbSNP: rs760265100

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000623763	SCV000741459	likely pathogenic	Inborn genetic diseases	2016-04-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001221841	SCV001393908	pathogenic	PMM2-congenital disorder of glycosylation	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 18 of the PMM2 protein (p.Thr18Ser). This variant is present in population databases (rs760265100, gnomAD 0.004%). This missense change has been observed in individual(s) with congenital disorder of glycosylation (PMID: 15844218, 16435227, 28139241). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 521048). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMM2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PMM2 function (PMID: 15844218). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507340	SCV001712852	likely pathogenic	not provided	2020-04-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001221841	SCV002555747	likely pathogenic	PMM2-congenital disorder of glycosylation	2022-06-08	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.53C>G (p.Thr18Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 230864 control chromosomes. c.53C>G has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1a (example Le Bizec_2005, Coman_2005, Perez-Cerda_2017, van den Boogert_2019). These data indicate that the variant is likely to be associated with disease. An experimental study found the variant PMM2 protein to have normal PPM activity, but in comparison to wild type PPM2 its activity was severely reduced in response to heat, suggesting it may have an impact on protein stability (Le Bizec_2005). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two laboratories classified the variant as likely pathogenic and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV001507340	SCV002601215	pathogenic	not provided	2024-02-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: T18S causes reduced protein thermostability (PMID: 15844218); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15844218, 16435227, 34828263, 25497157, 31589614, 34859900, 35789514, 28139241)
Fulgent Genetics, Fulgent Genetics	RCV001221841	SCV002806528	likely pathogenic	PMM2-congenital disorder of glycosylation	2021-09-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001221841	SCV004205290	likely pathogenic	PMM2-congenital disorder of glycosylation	2024-02-21	criteria provided, single submitter	clinical testing