Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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, |
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, |
RCV000576764 | SCV000743894 | pathogenic | PMM2-congenital disorder of glycosylation | 2017-07-28 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
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. |
Hudson |
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, |
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, |
RCV000254854 | SCV001712853 | pathogenic | not provided | 2019-09-08 | criteria provided, single submitter | clinical testing | PS3, PS4_Moderate, PM2, PP3, PP4 |
Victorian Clinical Genetics Services, |
RCV000576764 | SCV002767227 | pathogenic | PMM2-congenital disorder of glycosylation | 2022-02-02 | 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, |
RCV000576764 | SCV000733549 | pathogenic | PMM2-congenital disorder of glycosylation | no assertion criteria provided | clinical testing | ||
Natera, |
RCV000576764 | SCV001457172 | pathogenic | PMM2-congenital disorder of glycosylation | 2020-09-16 | no assertion criteria provided | clinical testing | |
Biochemical Molecular Genetic Laboratory, |
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, |
RCV000254854 | SCV001956357 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Prevention |
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. |