Submissions for variant NM_000303.3(PMM2):c.338C>T (p.Pro113Leu)

gnomAD frequency: 0.00001  dbSNP: rs80338700

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790784	SCV000230063	pathogenic	not provided	2016-04-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000008162	SCV000757675	pathogenic	PMM2-congenital disorder of glycosylation	2023-11-20	criteria provided, single submitter	clinical testing	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). 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: 9140401, 18948042, 21541725, 26014514). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000008162	SCV000915735	pathogenic	PMM2-congenital disorder of glycosylation	2018-04-25	criteria provided, single submitter	clinical testing	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.
Myriad Genetics, Inc.	RCV000008162	SCV001194051	pathogenic	PMM2-congenital disorder of glycosylation	2019-12-11	criteria provided, single submitter	clinical testing	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
CeGaT Center for Human Genetics Tuebingen	RCV000790784	SCV001247654	pathogenic	not provided	2017-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000008162	SCV001363462	pathogenic	PMM2-congenital disorder of glycosylation	2019-05-24	criteria provided, single submitter	clinical testing	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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000790784	SCV001447249	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000008162	SCV001752789	pathogenic	PMM2-congenital disorder of glycosylation	2021-06-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000790784	SCV001982062	pathogenic	not provided	2022-09-07	criteria provided, single submitter	clinical testing	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)
Revvity Omics, Revvity	RCV000008162	SCV002018868	pathogenic	PMM2-congenital disorder of glycosylation	2019-04-18	criteria provided, single submitter	clinical testing
3billion	RCV000008162	SCV002058132	pathogenic	PMM2-congenital disorder of glycosylation	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007723, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000420784, PMID:15520415, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.966, 3CNET: 0.984, PP3_P). A missense variant is a common mechanism associated with Congenital disorder of glycosylation (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000024, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000008162	SCV004204839	pathogenic	PMM2-congenital disorder of glycosylation	2024-03-05	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000008162	SCV005382272	pathogenic	PMM2-congenital disorder of glycosylation	2023-05-20	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000008162	SCV000028367	pathogenic	PMM2-congenital disorder of glycosylation	2001-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000008162	SCV000040581	not provided	PMM2-congenital disorder of glycosylation		no assertion provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003988	SCV001162014	pathogenic	Congenital cerebellar hypoplasia; Cerebellar ataxia; Cerebral palsy; Cerebral atrophy; Spasticity; Poor speech		no assertion criteria provided	research
Natera, Inc.	RCV000008162	SCV001457168	pathogenic	PMM2-congenital disorder of glycosylation	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952346	SCV004767215	pathogenic	PMM2-related disorder	2023-12-06	no assertion criteria provided	clinical testing	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.