Submissions for variant NM_000303.3(PMM2):c.368G>A (p.Arg123Gln) (rs141498002)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254854	SCV000321928	pathogenic	not provided	2021-05-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that R123Q affects protein stability, causes a 40% reduction of the protein half-life and results in no residual enzyme activity (Vega et al, 2011; Yuste-Checa et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30304743, 28671287, 31115488, 28807751, 10527672, 9497260, 11715002, 11156536, 26014514, 21541725, 22012410)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000576764	SCV000696495	pathogenic	Congenital disorder of glycosylation, type Ia	2016-08-04	criteria provided, single submitter	clinical testing	Variant summary: The PMM2 c.368G>A (p.Arg123Gln) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a deleterious outcome. This variant was found in 3/28750 control chromosomes at a frequency of 0.0001043, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMM2 variant (0.0055902). This variant has been reported in many CDG patients as compound heterozygotes with another pathogenic variant in trans. Functional studies showed that variant of interest led to null activity of the protein and classified the variant as one of the severe mutations. Taken together, this variant is classified as pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000576764	SCV000743894	pathogenic	Congenital disorder of glycosylation, type Ia	2017-07-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000576764	SCV000782487	uncertain significance	Congenital disorder of glycosylation, type Ia	2016-09-22	criteria provided, single submitter	clinical testing
Invitae	RCV000576764	SCV000950705	pathogenic	Congenital disorder of glycosylation, type Ia	2020-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 123 of the PMM2 protein (p.Arg123Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs141498002, ExAC 0.07%). This variant has been observed in many individuals affected with PMM2-CDG (PMID: 9497260, 21541725, 22012410,15844218). ClinVar contains an entry for this variant (Variation ID: 265255). Experimental studies have shown that this missense change reduces PMM2 enzyme activity and reduces protein stability (PMID: 21541725, 26014514). For these reasons, this variant has been classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000576764	SCV000993427	likely pathogenic	Congenital disorder of glycosylation, type Ia	2018-08-29	criteria provided, single submitter	research	ACMG codes: PS3, PM2, PP3, PP5
Myriad Women's Health, Inc.	RCV000576764	SCV001194243	pathogenic	Congenital disorder of glycosylation, type Ia	2019-12-24	criteria provided, single submitter	clinical testing	NM_000303.2(PMM2):c.368G>A(R123Q) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Sources cited for classification include the following: PMID 15844218, 11156536, 21541725, 11409861, 25497157, 17166182, 25355454 and 11715002. Classification of NM_000303.2(PMM2):c.368G>A(R123Q) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Baylor Genetics	RCV000576764	SCV001527206	pathogenic	Congenital disorder of glycosylation, type Ia	2018-10-16	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 9497260, 22012410, 10527672, 21541725, 28807751, 26014514]
Mayo Clinic Laboratories, Mayo Clinic	RCV000254854	SCV001712853	pathogenic	not provided	2019-09-08	criteria provided, single submitter	clinical testing	PS3, PS4_Moderate, PM2, PP3, PP4
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000576764	SCV000733549	pathogenic	Congenital disorder of glycosylation, type Ia		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000576764	SCV001457172	pathogenic	Congenital disorder of glycosylation, type Ia	2020-09-16	no assertion criteria provided	clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City	RCV000576764	SCV001469145	pathogenic	Congenital disorder of glycosylation, type Ia	2020-09-10	no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV000254854	SCV001956357	pathogenic	not provided		no assertion criteria provided	clinical testing