chr16-8811153-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 15P and 1B. PM1PM2PM5PP3PP5_Very_StrongBP4
The ENST00000268261.9(PMM2):c.422G>A(p.Arg141His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 1,570,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R141C) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.0037 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0050 ( 0 hom. )
Consequence
PMM2
ENST00000268261.9 missense
ENST00000268261.9 missense
Scores
12
3
3
Clinical Significance
Conservation
PhyloP100: 9.79
Genes affected
PMM2 (HGNC:9115): (phosphomannomutase 2) The protein encoded by this gene catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate, which is a precursor to GDP-mannose necessary for the synthesis of dolichol-P-oligosaccharides. Mutations in this gene have been shown to cause defects in glycoprotein biosynthesis, which manifests as carbohydrate-deficient glycoprotein syndrome type I. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000268261.9
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-8811152-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 550780.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Pathogenic=1, Uncertain_significance=1}.
PP3
Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
PP5
Variant 16-8811153-G-A is Pathogenic according to our data. Variant chr16-8811153-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8811153-G-A is described in Lovd as [Pathogenic]. Variant chr16-8811153-G-A is described in Lovd as [Pathogenic]. Variant chr16-8811153-G-A is described in Lovd as [Benign].
BP4
Computational evidence support a benign effect (MetaRNN=0.020802349). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PMM2 | NM_000303.3 | c.422G>A | p.Arg141His | missense_variant | 5/8 | ENST00000268261.9 | NP_000294.1 | |
| PMM2 | XM_047434215.1 | c.173G>A | p.Arg58His | missense_variant | 3/6 | XP_047290171.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PMM2 | ENST00000268261.9 | c.422G>A | p.Arg141His | missense_variant | 5/8 | 1 | NM_000303.3 | ENSP00000268261 | P1 |
Frequencies
GnomAD3 genomes 0.00366 AC: 557AN: 152168Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00407 AC: 785AN: 192974Hom.: 0 AF XY: 0.00419 AC XY: 432AN XY: 103054
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GnomAD4 exome AF: 0.00503 AC: 7141AN: 1418658Hom.: 0 Cov.: 31 AF XY: 0.00489 AC XY: 3432AN XY: 702556
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GnomAD4 genome 0.00366 AC: 557AN: 152286Hom.: 0 Cov.: 33 AF XY: 0.00388 AC XY: 289AN XY: 74468
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:57Other:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
PMM2-congenital disorder of glycosylation Pathogenic:37Other:3
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Inherited Metabolic Diseases, Karolinska University Hospital | Apr 02, 2020 | - - |
| Pathogenic, no assertion criteria provided | research | Dobyns Lab, Seattle Children's Research Institute | Feb 18, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | May 06, 2024 | A PMM2 c.422G>A (p.Arg141His) variant was identified in a heterozygous state. This variant has been reported in numerous individuals with PMM2-related congenital disorders of glycosylation (Matthijs G et al., PMID: 9497260; Kjaergaard S et al., PMID: 11517108; Romano S et al., PMID: 19357119; Vega AI et al., PMID: 21541725; Barone R et al., PMID: 25355454; Matthijs G et al., PMID: 9140401; de Lonlay P et al., PMID: 11134235) and is one of the most frequent pathogenic variants in this gene. The PMM2 c.422G>A (p.Arg141His) variant has been reported in the ClinVar database as pathogenic by several submitters (ClinVar ID: 7706). The global population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.4%, which is consistent with the carrier frequency for this disorder based on the recent estimated incidence of disease (Pajusalu S et al., PMID: 34447415). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PMM2 function. In support of this prediction, functional studies show that the p.Arg141His variant affects protein stability, indicating that this variant impacts protein function (Vega AI et al., PMID: 21541725; Yuste-Checa P et al., PMID: 26014514). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 06, 2021 | Variant summary: PMM2 c.422G>A (p.Arg141His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0041 in 192974 control chromosomes. c.422G>A has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1a (example, Matthijs_1997, Barone_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of PMM2 enzyme activity in one study (example, Vega_2011) and an oligomerization profile with a predominant aggregate fraction, less dimerization, nearly non-detectable enzymatic activities, and shorter degradation time in another study (example, Yuste-Checa_2015). Thus, variant severly affected both the folding as well as catalytic properties of the PMM2 protein . Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant classified as Pathogenic and reported on 06-29-2018 by Lab or GTR ID 1238. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Pediatric Metabolic Diseases, Hacettepe University | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 05, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 141 of the PMM2 protein (p.Arg141His). This variant is present in population databases (rs28936415, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with PMM2-CDG (PMID: 9497260, 11517108, 19357119, 21541725, 25355454). It is commonly reported in individuals of European ancestry (PMID: 9497260, 11517108, 19357119, 21541725, 25355454). ClinVar contains an entry for this variant (Variation ID: 7706). 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: 21541725, 26014514). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Courtagen Diagnostics Laboratory, Courtagen Life Sciences | Feb 18, 2015 | - - |
| Pathogenic, criteria provided, single submitter | research | Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris | Jan 04, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 19, 2019 | NM_000303.2(PMM2):c.422G>A(R141H) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Please note that in the homozygous state, R141H may be associated with fetal demise. Sources cited for classification include the following: PMID 11058895, 9497260, 10854097, 21541725, 9781039, 26488408, 15844218, 10922383, 26014514, and 10386614. Classification of NM_000303.2(PMM2):c.422G>A(R141H) 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. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2007 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 21, 2024 | The p.Arg141His variant in PMM2 has been reported in several compound heterozygous individuals with congenital disorder of glycosylation type Ia and is one of the most frequent pathogenic variants in patients with this disorder (Matthijs 1997 PMID: 9140401, Matthijs 1998 PMID: 9497260, de Lonlay 2001 PMID: 11134235). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 7706) and has been identified in 0.7% (472/61238) of Finnish chromosomes and 0.6% (6521/1152934) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). However, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide evidence that this variant causes complete loss of enzyme activity (Vega 2011 PMID: 21541725, Andreotti 2015 PMID: 26488408). The p.Arg141His variant has never been observed in homozygosity, suggesting that the total absence of PMM2 activity is not compatible with life (Matthijs 1998 PMID: 9497260). Computational prediction tools and conservation analyses suggests that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital disorder of glycosylation type Ia. ACMG/AMP Criteria applied: PM3_Very Strong, PS3_Moderate, PP4, PP3. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 24, 2018 | The PMM2 c.422G>A (p.Arg141His) missense variant is well-documented as the most common pathogenic variant found in patients with PMM2-associated congenital disorders of glycosylation (also known as CDG-1a) (Sparks et al. 2015). The p.Arg141His variant was first described by Matthijs et al. (1997) in a group of 33 unrelated individuals with confirmed phosphomannomutase deficiency. In this study, the p.Arg141His variant was identified in a compound heterozygous state in ten affected individuals. A review by Matthijs et al. (2000) looking at over 249 patients from six different studies and 23 different countries concluded that the p.Arg141His variant accounts for 37 percent of all disease-associated alleles. This variant is typically observed in a compound heterozygous state in patients with severe phenotypes and has never been reported in a homozygous state (Sparks et al. 2015). When expressed in vitro, the residual activity of the p.Arg141His recombinant protein is almost zero and thus supports the inference that homozygosity for this mutation is lethal early in development. This variant also shows a decreased binding affinity for the normal substrate and results in a significantly less stable protein compared to wild type (Pirard et al. 1999). The p.Arg141His variant is frequent in most populations and is reported at a frequency of 0.02756 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence the p.Arg141His variant is classified as pathogenic for congenital disorders of glycosylation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | The PMM2 c.422G>A (p.R141H) pathogenic variant has previously been reported in the compound heterozygous state in congenital disorder of glycosylation type Ia, also called PMM2-congenital disorder of glycosylation (PMM2-CDG) (PMID: 9140401; 9497260; 9781039; 11058895; 11134235; 11517108). - |
| Pathogenic, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 21, 2021 | DNA sequence analysis of the PMM2 gene demonstrated a sequence change, c.422G>A, in exon 5 that results in an amino acid change, p.Arg141His. The p.Arg141His sequence change has been observed in 0.4% of individuals in the gnomAD database, in the heterozygous state, and is regarded as the most common pathogenic variant found in patients with PMM2-related congenital disorders of glycosylation (PMID: 20301289). The p.Arg141His change affects a highly conserved amino acid residue located in a domain of the PMM2 protein that is known to be functional. The p.Arg141His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT PolyPhen2, Align GVGD, REVEL). This pathogenic sequence change has previously been described in an estimated 40% of individuals with PMM2-related congenital disorders of glycosylation (CDG), in the compound heterozygous state with a second variant (PMID: 20301289, 21541725). Functional studies have also demonstrated that the p.Arg141His change reduces protein stability and enzymatic activity in vitro (PMID: 26014514) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic and reported on 02-19-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Oct 13, 2022 | This variant has been reported in the literature as a compound heterozygote in several individuals with Congenital disorder of glycosylation type Ia (CDG-Ia) and segregating with disease in affected family members. Of note, at least one publication notes that this variant is the most common pathogenic variant for this condition (Selected publications: Matthijs 1997 PMID:9140401, van Ommenn 2000 PMID:10700701, Briones 2001 PMID:11589167, Kjaergard 2001 PMID:11517108, Barone 2008 PMID:18629883, Vega 2011 PMID:21541725, Bastaki 2018 PMID:28940310). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.7% (82/10618) (https://gnomad.broadinstitute.org/variant/16-8811153-G-A?dataset=gnomad_r3). Please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as Pathogenic (Variation ID:7706). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In addition, functional studies support that this variant will impact the protein by affecting folding and catalytic activity (Vega 2011 PMID:21541725, Yuste-Checa 2015 PMID:26014514). In summary, this variant is classified as pathogenic based on the data above. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Arab Genomic Studies, Sheikh Hamdan Award for Medical Sciences | Jul 15, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 13, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Oct 06, 2021 | ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 06, 2022 | Criteria applied: PS3,PS4,PM5_SUP,PP3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Aug 13, 2018 | This variant is found in the compound heterozygous state in approximately 40% of individuals with Congenital disorder of glycosylation Type 1A of European ancestry (PMID: 20301289). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.39% (891/224376). The c.422G>A (p.Arg141His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Functional characterization in multiple studies indicates that the p.Arg141His variant negatively impacts protein function including stability and enzymatic activity (PMID: 21541725, 26488408, 26014514). Based on the available evidence, the c.422G>A (p.Arg141His) variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | Feb 12, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 08, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Mar 31, 2022 | 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 histidine. (I) 0251 – This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (891 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (7 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a minor amino acid change. (SP) 0600 - Variant is located in the annotated eukaryotic phosphomannomutase domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg141Cys) variant has been classified as likely pathogenic by multiple clinical diagnostic laboratories (ClinVar). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been consistently classified as pathogenic by multiple clinical diagnostic laboratories and is the most common PMM2 pathogenic variant in Northern Europeans (ClinVar, GeneReviews). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Nov 18, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | May 10, 2021 | The PMM2 c.422G>A variant is classified as PATHOGENIC (PM3, PP3, PS3, PS4) The PMM2 c.422G>A variant is a single nucleotide change in exon 5 of the PMM2 gene, which is predicted to change the amino acid arginine at position 141 in the protein to histidine. This is a recurrent variant and one of the most common PMM2 mutations (PS4). It is predicted to be homozygous lethal, so is only found in compound heterozygous state (PM3). Functional studies have demonstrated reduced enzyme stability and catalytic activity compared with wild type (PMID:21541725) (PS3). This variant is in dbSNP (rs28936415) and has been reported in population databases (gnomAD 891/224376 alleles, 0 homozygotes). This variant has been reported in ClinVar as pathogenic by multiple other diagnostic laboratories (ClinVar Variation ID: 22745). It is also classed as damaging for congenital disorder of glycosylation type 1a in HGMD (CM971228). Computational predictions support a deleterious effect on the gene or gene product (PP3). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
| Pathogenic, criteria provided, single submitter | research | Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL) | Apr 27, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 14, 2017 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.397%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.78). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007706). A different missense change at the same codon (p.Arg141Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000550780). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:11
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PMM2 p.R141H is one of the most frequent pathogenic variants found to cause congenital disorder of glycosylation type 1a (CDG1a) and is reported in ~40% of European CDG1a cases. This variant has only been found in the compound heterozygous state, suggesting that homozygosity for the p.A141H variant would be lethal (Matthijs_1998_PMID:9497260; Kjaergaard_1998_PMID:9781039). The variant was identified in dbSNP (ID: rs28936415) and ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics, Laboratory for Molecular Medicine, Genetic Services Laboratory, University of Chicago and 15 other laboratories). The variant was identified in control databases in 891 of 224376 chromosomes at a frequency of 0.003971 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 177 of 21196 chromosomes (freq: 0.008351), Ashkenazi Jewish in 71 of 9376 chromosomes (freq: 0.007573), European (non-Finnish) in 511 of 94084 chromosomes (freq: 0.005431), Other in 27 of 6220 chromosomes (freq: 0.004341), Latino in 64 of 30676 chromosomes (freq: 0.002086), South Asian in 24 of 25492 chromosomes (freq: 0.000942), African in 15 of 20700 chromosomes (freq: 0.000725), and East Asian in 2 of 16632 chromosomes (freq: 0.00012). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.R141 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. Functional studies have demonstrated loss of PMM2 protein activity from the p.R141H variant (Vega_2011_PMID:21541725; Yuste-Checa_2015_PMID:26014514). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 11, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | PMM2: PM3:Very Strong, PM2, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 20, 2023 | PP3, PM3_very_strong, PS3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Dec 18, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Feb 06, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 12, 2024 | One of the most common pathogenic PMM2 variants reported among European individuals with CDG-1a, but has only been identified in the compound heterozygous state and is predicted to be homozygous lethal (PMID: 11530212, 11517108); Published functional studies demonstrate a damaging effect with reduced enzyme stability and catalytic activity below detection limits (PMID: 21541725); This variant is associated with the following publications: (PMID: 25192236, 20981092, 28373276, 28940310, 34670123, 34828263, 22975760, 10700701, 25333069, 21228398, 11530212, 9140401, 19357119, 11517108, 11589167, 27053713, 28139241, 23988505, 25108116, 16376131, 18629883, 19165618, 28425223, 28566178, 28820871, 30609409, 30487145, 30991241, 31474318, 31628766, 31981409, 31980526, 32595772, 32581362, 33580824, 11409861, 34277356, 33960646, 34426522, 32841164, 32064623, 31589614, 33163565, 32874916, 31736265, 33643843, 33204593, 33413482, 21541725, 32860008, 34055813, 33726816, 35279850, 34445196, 36099812, 36239000, 36773065, 35531120, 37541188, 35281664, 31902100, 37301908, 31391289, 26014514, 26488408) - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 13, 2021 | The c.422G>A (p.R141H) alteration is located in coding exon 5 of the PMM2 gene. This alteration results from a G to A substitution at nucleotide position 422, causing the arginine (R) at amino acid position 141 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD) database, the PMM2 c.422G>A alteration was observed in 0.4% (891/224,376) of total alleles studied, with a frequency of 0.84% (177/21,196) in the European (Finnish) subpopulation. This missense alteration is the most frequent disease-causing PMM2 alteration and has been reported in several populations (Matthijs, 1997; Schollen, 2000; Vuillaumier-Barrot, 2000; Bohles, 2001; Quelhas, 2006). While the p.R141H alteration has been reported in compound heterozygosity with a second alteration in numerous patients with PMM2-related congenital disorder of glycosylation, no patients homozygous for this alteration have been reported, likely because it is a severe mutation and homozygosity would be lethal early in development (Matthijs, 1999). This amino acid position is highly conserved in available vertebrate species. The p.R141 amino acid is a crucial part of the distal phosphate binding site in the cap domain of α-PMM2, and loss of the positive charge at this location would impair substrate binding (Silvaggi, 2006). Functional analysis demonstrated that the PMM2 protein product harboring the p.R141H alteration has no residual enzymatic activity when expressed in vitro. Further, the p.R141H protein product had a shortened half-life compared to wild type protein, suggesting that the alteration affects protein stability (Vega, 2011). The p.R141H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
PMM2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 26, 2024 | The PMM2 c.422G>A variant is predicted to result in the amino acid substitution p.Arg141His. This variant has been documented as causative for autosomal recessive congenital disorder of glycosylation type Ia (CDG-Ia), and is one of the most frequent pathogenic variants reported in the PMM2 gene (Matthijs et al. 1997. PubMed ID: 9140401; Kjaergaard et al. 2001. PubMed ID: 11517108; Vega et al. 2011. PubMed ID: 21541725). The c.422G>A (p.Arg141His) variant is also reported as c.425G>A (p.Arg141His) in the literature. Functional in vitro studies on this variant have demonstrated that it severely impacts protein stability and activity (Vega et al. 2011. PubMed ID: 21541725). Additionally, a mouse model (compound heterozygous for variants corresponding to the human p.Arg141His and p.Phe119Leu variants) demonstrated prenatal death and significantly stunted growth in animals due to protein glycosylation deficiencies (Chan et al. 2016. PubMed ID: 27053713). Of note, the c.422G>A variant has been observed with a subpopulation (European) frequency up to ~0.8% in a large database of individuals with unknown phenotype. However, no homozygotes have been reported to date, and the c.422G>A (p.Arg141His) variant is suspected to be embryonically lethal when present in the homozygous state (Matthijs et al. 1998. PubMed ID: 9497260; Thiel et al. 2006. PubMed ID: 16847317). This variant is classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/7706/). Taken together, we interpret this variant as pathogenic. - |
Congenital disorder of glycosylation Pathogenic:1
| Pathogenic, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | NM_000303.2:c.422G>A in the PMM2 gene has an allele frequency of 0.008 in European(Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that p.Arg141His has reduced protein stability and enzymatic activity in vitro (PMID: 26014514).It was detected in multiple individuals with autosomal recessive PMM2-CDG, compound heterozygous with c.710C>T (p.Thr237Met), c.484C>T (p.Arg162Trp), c.722G>C (p.Cys241Ser), c.677C>G (p.Thr226Ser) (PMID: 21541725).Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PM3_Strong; PS3; PP4 - |
Cerebellar ataxia;C0007789:Cerebral palsy;C0026838:Spasticity;C0235946:Cerebral atrophy;C1848207:Poor speech;C5231391:Congenital cerebellar hypoplasia Pathogenic:1
| Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
Congenital cerebellar hypoplasia Pathogenic:1
| Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Focal segmental glomerulosclerosis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Lab, Nemours Children's Health, Delaware | Oct 22, 2019 | This missense variant (c.422G>A, p.Arg141His) has been observed at very low frequency in population databases (gnomAD). It has been reported in the literature (PMID 24424129, 9140401, 30061496). Variant prediction programs suggest a deleterious effect, and functional studies support this (PMID 21541725). This change was found in an affected patient. - |
Cerebellar ataxia;C0011849:Diabetes mellitus;C0026850:Muscular dystrophy;C5231391:Congenital cerebellar hypoplasia Pathogenic:1
| Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
Cerebellar ataxia Pathogenic:1
| Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
Congenital disorder of glycosylation type I Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jun 10, 2022 | The c.422G>A;p.(Arg141His)missense change one of most frequently variant associated with the phenotype described in the gene and ClinVar contains an entry for this variant (ClinVar ID: 7706; PMID: 32860008; 32581362; 31474318; 28940310; 28373276; 25333069; 22975760; 21228398; 19357119; 11530212; 10700701; 9140401) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 21541725, 26488408, 26014514) - PS3. The variant is present at low allele frequencies population databases (rs28936415– gnomAD 0.03660%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Arg141His) was detected in trans with a Pathogenic variant (PMID: 9140401; 9497260; 9781039; 11058895; 11134235; 11517108; 19357119; 20301289; 21541725; 25355454) - PM3_very strong. Pathogenic missense variant in this residue have been reported and classified as Pathogenic by ACMG criteria (c.421C>T (p.Arg141Cys) - PMID: 15844218) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
.;H
MutationTaster
Benign
A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Benign
D;D
Sift4G
Uncertain
D;D
Polyphen
0.99
.;D
Vest4
MVP
MPC
0.041
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at