16-8806398-C-T
Variant summary
Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000303.3(PMM2):c.338C>T(p.Pro113Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,609,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P113T) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000303.3 missense
Scores
Clinical Significance
Conservation
Publications
- congenital disorder of glycosylation type IInheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
- PMM2-congenital disorder of glycosylationInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 19 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PMM2 | NM_000303.3 | c.338C>T | p.Pro113Leu | missense_variant | Exon 4 of 8 | ENST00000268261.9 | NP_000294.1 | |
| PMM2 | XM_047434215.1 | c.89C>T | p.Pro30Leu | missense_variant | Exon 2 of 6 | XP_047290171.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152106Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000239 AC: 6AN: 251400 AF XY: 0.0000294 show subpopulations
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1457072Hom.: 0 Cov.: 28 AF XY: 0.0000193 AC XY: 14AN XY: 725294 show subpopulations
Age Distribution
GnomAD4 genome 0.0000197 AC: 3AN: 152106Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74306 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
PMM2-congenital disorder of glycosylation Pathogenic:12Other:1
NM_000303.2(PMM2):c.338C>T(P113L) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Sources cited for classification include the following: PMID 21541725, 9140401, 11156536 and 15844218. Classification of NM_000303.2(PMM2):c.338C>T(P113L) 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.‚Äã -
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The PMM2 c.338C>T; p.Pro113Leu variant (rs80338700, ClinVar variation ID: 7723) is reported in the literature in numerous individuals affected with PMM2 related congenital disorder of glycosylation (PMM2-CDG; selected references: Erlandson 2001, Matthijs 1997) and is considered to be a common pathogenic variant (Lam 2005). This variant is found in the general population with an overall allele frequency of 0.002% (6/251,400 alleles) in the Genome Aggregation Database (v2.1.1). In vitro functional analyses demonstrate a reduction in PMM2 activity and affects dimer interactions (Vega 2011, Yuste-Checa 2015). Computational analyses predict that this variant is deleterious (REVEL: 0.966). Based on available information, this variant is considered to be pathogenic. References: Erlandson A et al. Scandinavian CDG-Ia patients: genotype/phenotype correlation and geographic origin of founder mutations. Hum Genet. 2001 May;108(5):359-67. PMID: 11409861. Lam C et al. PMM2-CDG. 2005 Aug 15 [Updated 2021 May 20]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1110/ Matthijs G et al. Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome). Nat Genet. 1997 May;16(1):88-92. PMID: 9140401. Vega AI et al. Expression analysis revealing destabilizing mutations in phosphomannomutase 2 deficiency (PMM2-CDG): expression analysis of PMM2-CDG mutations. J Inherit Metab Dis. 2011 Aug;34(4):929-39. PMID: 21541725. Yuste-Checa P et al. The Effects of PMM2-CDG-Causing Mutations on the Folding, Activity, and Stability of the PMM2 Protein. Hum Mutat. 2015 Sep;36(9):851-60. PMID: 26014514. -
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 113 of the PMM2 protein (p.Pro113Leu). This variant is present in population databases (rs80338700, gnomAD 0.01%). This missense change has been observed in individuals with PMM2-related congenital disorder of glycosylation (PMM2-CDG, also known as CDG type Ia) (PMID: 9140401, 11058895, 18948042, 21541725). ClinVar contains an entry for this variant (Variation ID: 7723). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 9140401, 18948042, 21541725, 26014514). For these reasons, this variant has been classified as Pathogenic. -
The observed missense variant c.338C>T(p.Pro113Leu) in PMM2 gene has been previously reported in both homozygous and compound heterozygous states in multiple individuals affected with congenital disorder of glycosylation (Vega et al., 2011; Le Bizec et al., 2005; Matthijs et al., 2000; Grünewald et al., 2001; Pérez-Dueñas et al., 2009; Yuste-Checa et al., 2015). Experimental studies showed this variant to result in reduced enzyme activity, reduced half-life, and disruption of dimer formation (Vega et al., 2011; Grünewald et al., 2001; Yuste-Checa et al., 2015). The p.Pro113Leu variant is present with allele frequency of 0.002% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease Causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Pro113Leu in PMM2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Pro at position 113 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
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Variant summary: PMM2 c.338C>T (p.Pro113Leu) 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 2.4e-05 in 251400 control chromosomes. c.338C>T has been reported in the literature in multiple individuals affected with infantile multisystem CDG-1a (e.g. Matthijs_2000, Grunewald_2001, Vega_2011). These data indicate that the variant is very likely to be associated with disease. The variant has been shown in experimental studies to result in reduced enzyme activity, reduced half-life, and disruption of dimer formation (Grunewald_2001, Vega_2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007723 /PMID: 9140401 /3billion dataset).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 18948042, 21541725).Different missense changes at the same codon (p.Pro113Ala, p.Pro113Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000420784 /PMID: 15520415). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
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Across a selection of the available literature, the PMM2 c.338C>T (p.Pro113Leu) variant has been reported in at least four studies and is found in a total of 13 probands, including one in a homozygous state and 12 in a compound heterozygous state (Matthijs et al. 1997; Briones et al. 2001; Le Bizec et al. 2005; Vega et al. 2011). Probands exhibited a range of phenotypes, including cerebellar atrophy, hypotonia, and lipodystrophy (Vega et al. 2011). In vitro analysis of the p.Pro113Leu variant found 43% residual activity compared to controls and 19% residual activity when in a homozygous state in proband fibroblasts (Vega et al. 2011). The p.Pro113Leu variant was also found to affect oligomerization of PMM2 subunits and PMM2 protein dimerization (Yuste-Checa et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.000349 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Pro113Leu 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. -
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not provided Pathogenic:4
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Published functional studies demonstrate a damaging effect as P113L results in reduced PMM activity and a reduced half-life (Vega et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11156536, 34828263, 25525159, 26014514, 11589167, 22975760, 9140401, 11058896, 15844218, 18948042, 11916319, 11058895, 32581362, 11409861, 32064623, 31589614, 33643843, 33413482, 21541725) -
PMM2-related disorder Pathogenic:1
The PMM2 c.338C>T variant is predicted to result in the amino acid substitution p.Pro113Leu. This variant was reported with a second known or potential causative variant in individuals with congenital disorder of glycosylation (see, for example, Matthijs et al. 1997. PubMed ID: 9140401; Yuste-Checa et al. 2015. PubMed ID: 26014514; Starosta et al. 2021. PubMed ID: 33413482; Lipiński et al. 2021. PubMed ID: 33643843; Pérez-Dueñas et al. 2008. PubMed ID: 18948042). In vitro functional analyses indicate that the p.Pro113Leu change results in loss of PMM2 activity (Vega et al. 2011. PubMed ID: 21541725; Yuste-Checa et al. 2015. PubMed ID: 26014514; Segovia-Falquina et al. 2022. PubMed ID: 35789514). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. -
Cerebellar ataxia;C0007789:Cerebral palsy;C0026838:Spasticity;C0235946:Cerebral atrophy;C1848207:Poor speech;C5231391:Congenital cerebellar hypoplasia Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at