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

gnomAD frequency: 0.00017  dbSNP: rs141498002

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254854	SCV000321928	pathogenic	not provided	2023-11-16	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 (PMID: 26014514, 21541725); 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: 21541725, 28807751, 30304743, 28671287, 34930662, 22012410, 11156536, 11715002, 10527672, 31115488, 28915903, 25497157, 25355454, 17166182, 15844218, 11409861, 28122681, 10922383, 20652024, 12705494, 32071842, 9497260, 26014514)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000576764	SCV000696495	pathogenic	PMM2-congenital disorder of glycosylation	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	PMM2-congenital disorder of glycosylation	2017-07-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000576764	SCV000950705	pathogenic	PMM2-congenital disorder of glycosylation	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 123 of the PMM2 protein (p.Arg123Gln). This variant is present in population databases (rs141498002, gnomAD 0.02%). This missense change has been observed in individual(s) with PMM2-CDG (PMID: 9497260, 15844218, 21541725, 22012410). 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: 265255). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PMM2 protein function. Experimental studies have shown that this missense change affects PMM2 function (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	PMM2-congenital disorder of glycosylation	2018-08-29	criteria provided, single submitter	research	ACMG codes: PS3, PM2, PP3, PP5
Myriad Genetics, Inc.	RCV000576764	SCV001194243	pathogenic	PMM2-congenital disorder of glycosylation	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	PMM2-congenital disorder of glycosylation	2024-03-30	criteria provided, single submitter	clinical testing
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
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000576764	SCV002767227	pathogenic	PMM2-congenital disorder of glycosylation	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of glycosylation type Ia (MIM# 212065). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 – This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (30 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position to leucine has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the Phosphomannomutase annotated domain (NCBI). (I) 0801 – This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported as pathogenic in patients with congenital disorder of glycosylation type Ia (ClinVar, PMID: 9497260, 15844218, 22012410). (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV004021026	SCV005009708	pathogenic	Inborn genetic diseases	2022-01-28	criteria provided, single submitter	clinical testing	The c.368G>A (p.R123Q) alteration is located in exon 5 (coding exon 5) of the PMM2 gene. This alteration results from a G to A substitution at nucleotide position 368, causing the arginine (R) at amino acid position 123 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (30/223998) total alleles studied. The highest observed frequency was 0.02% (18/94022) of European (non-Finnish) alleles. This mutation has been reported in conjunction with multiple PMM2 missense alterations in individuals with PMM2-related congenital disorder of glycosylation (Matthijs, 1998; Westphal, 2001; Le Bizec, 2005; Vega, 2011)._x000D_ _x000D_ Reference:_x000D_ _x000D_ Westphal V, et al. Genet Med. Nov-Dec 2001;3(6):393-8. This amino acid position is highly conserved in available vertebrate species. Analysis of this variant in both E. coli and S. cerevisiae demonstrated reduced or absent residual activity when compared to wildtype (Westphal, 2001; Vega, 2011; Yuste-Checa, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000576764	SCV000733549	pathogenic	PMM2-congenital disorder of glycosylation		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000576764	SCV001457172	pathogenic	PMM2-congenital disorder of glycosylation	2020-09-16	no assertion criteria provided	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000576764	SCV001469145	pathogenic	PMM2-congenital disorder of glycosylation	2020-09-10	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000254854	SCV001956357	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004755832	SCV005361129	pathogenic	PMM2-related disorder	2024-03-31	no assertion criteria provided	clinical testing	The PMM2 c.368G>A variant is predicted to result in the amino acid substitution p.Arg123Gln. This variant was reported in multiple individuals with congenital disorder of glycosylation 1a (see, for example, Matthijs et al. 1998. PubMed ID: 9497260; Vega et al. 2011. PubMed ID: 21541725; Casado et al. 2012. PubMed ID: 22012410; Vicario et al. 2017. PubMed ID: 28807751). In vitro function analysis indicates that this nucleotide change abolishes PMM2 enzyme activity (Vega et al. 2011. PubMed ID: 21541725; Yuste-Checa et al. 2015. PubMed ID: 26014514). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.