Submissions for variant NM_000303.3(PMM2):c.357C>A (p.Phe119Leu)

gnomAD frequency: 0.00003  dbSNP: rs80338701

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790706	SCV000230900	pathogenic	not provided	2013-06-07	criteria provided, single submitter	clinical testing
Courtagen Diagnostics Laboratory, Courtagen Life Sciences	RCV000008150	SCV000236531	pathogenic	PMM2-congenital disorder of glycosylation	2015-01-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000008150	SCV000399673	pathogenic	PMM2-congenital disorder of glycosylation	2017-04-27	criteria provided, single submitter	clinical testing	As summarized by Matthijs et al. (2000), the PMM2 c.357C>A (p.Phe119Leu) missense variant has been reported across the literature in at least 82 patients with PMM2-associated congenital disorders of glycosylation from 68 families in 11 countries, and is considered a founder variant in Scandinavian populations. The variant was identified in a compound heterozygous state with the common p.Arg141His variant in 68 patients from 56 families; patients compound heterozygous for these variants account for 81%, 50%, 32%, and 30% of the genotypes observed in Denmark, the Netherlands, Sweden, and Germany, respectively. The p.Phe119Leu variant has also been reported in a homozygous state in four patients. The p.Phe119Leu variant is reported at a frequency of 0.00023 in the European (non-Finnish) population of the Exome Aggregation Consortium. In vitro functional studies in E. coli BL21 (DE3) cells demonstrated that the p.Phe119Leu variant results in 25% residual enzyme activity, reduced protein activity and stability, and altered protein quaternary structure as compared to wild type (Kjaergaard et al. 1999; Andreotti et al. 2013). Based on the collective evidence, the p.Phe119Leu variant is classified as pathogenic for congenital disorders of glycosylation, specifically for congenital disorders of glycosylation, type 1a. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000008150	SCV000680023	pathogenic	PMM2-congenital disorder of glycosylation	2017-07-05	criteria provided, single submitter	clinical testing	The NM_000303.2(PMM2):c.357C>A missense variant was identified in exon 5 of the PMM2 gene. This substitution creates a minor amino acid change from a phenylalanine to a leucine at position 119, NP_000294.1(PMM2):p.(Phe119Leu). The phenylalanine at this position has moderate conservation (100 vertebrates, UCSC). In silico tools predict this variant to be deleterious (Polyphen, SIFT, Mutation Taster). This variant is not present in the gnomAD population database. It is situated in a PMM domain. It has been previously reported in multiple families with congenital disorder of glycosylation (ClinVar). In addition, functional studies show this variant in compound heterozygous state weakens quartenary structure, destabilises the protein and reduces enzyme activity (Andreotti. et al., (2013) and Noelle et al., (2005)). Based on current information and in association with the NM_000303.2(PMM2):c.470T>C missense variant, this variant has been classified as PATHOGENIC. The presence of these two variants suggests a possible compound heterozygous mode of inheritance which is consistent with congenital disorder of glycosylation.
Ambry Genetics	RCV000624449	SCV000742672	pathogenic	Inborn genetic diseases	2014-09-07	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000008150	SCV000743893	pathogenic	PMM2-congenital disorder of glycosylation	2014-10-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000008150	SCV000807615	pathogenic	PMM2-congenital disorder of glycosylation	2024-03-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000008150	SCV000833921	pathogenic	PMM2-congenital disorder of glycosylation	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 119 of the PMM2 protein (p.Phe119Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with PMM2-CDG (CDG-Ia) (PMID: 9140401, 9781039, 10801058, 11517108, 15645285). ClinVar contains an entry for this variant (Variation ID: 7711). 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 80%. Experimental studies have shown that this missense change affects PMM2 function (PMID: 24498599, 26488408, 27053713). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000008150	SCV000920013	pathogenic	PMM2-congenital disorder of glycosylation	2018-05-11	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.357C>A (p.Phe119Leu) 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 3.2e-05 in 30952 control chromosomes (gnomAD). The variant, c.357C>A, has been reported in the literature in multiple individuals affected with Congenital Disorder of Glycosylation Type 1a (Kjaergaard_1998). 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 10%-<30% of normal activity. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000008150	SCV001193852	pathogenic	PMM2-congenital disorder of glycosylation	2019-12-11	criteria provided, single submitter	clinical testing	NM_000303.2(PMM2):c.357C>A(F119L) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Sources cited for classification include the following: PMID 24498599, 9781039 and 9140401. Classification of NM_000303.2(PMM2):c.357C>A(F119L) 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.
CeGaT Center for Human Genetics Tuebingen	RCV000790706	SCV001335043	pathogenic	not provided	2020-03-01	criteria provided, single submitter	clinical testing
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000008150	SCV001435295	pathogenic	PMM2-congenital disorder of glycosylation	2020-04-02	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000790706	SCV001446581	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000790706	SCV001818601	pathogenic	not provided	2022-06-06	criteria provided, single submitter	clinical testing	Functional studies demonstrate a damaging effect with disruption of dimerization and significantly reduced enzyme activity (Andreotti et al., 2013); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22975760, 26488408, 27053713, 15645285, 30061496, 9781039, 9497260, 12705494, 11409861, 10854097, 15844218, 28373276, 27535533, 9140401, 11517108, 32304219, 32064623, 33643843, 32685345, 33726816, 33413482, 24498599)
Centogene AG - the Rare Disease Company	RCV000008150	SCV002059827	pathogenic	PMM2-congenital disorder of glycosylation	2020-02-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000008150	SCV002810425	pathogenic	PMM2-congenital disorder of glycosylation	2024-02-27	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000790706	SCV005197194	pathogenic	not provided	2023-12-18	criteria provided, single submitter	clinical testing
OMIM	RCV000008150	SCV000028355	pathogenic	PMM2-congenital disorder of glycosylation	1998-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000008150	SCV000040582	not provided	PMM2-congenital disorder of glycosylation		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000008150	SCV000733548	pathogenic	PMM2-congenital disorder of glycosylation		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000008150	SCV000745881	pathogenic	PMM2-congenital disorder of glycosylation	2017-06-21	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000008150	SCV001457170	pathogenic	PMM2-congenital disorder of glycosylation	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000790706	SCV001955324	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000790706	SCV001970857	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004755719	SCV005346545	pathogenic	PMM2-related disorder	2024-04-24	no assertion criteria provided	clinical testing	The PMM2 c.357C>A variant is predicted to result in the amino acid substitution p.Phe119Leu. This variant, when present in the compound heterozygous or homozygous states, has been repeatedly reported to be causative for congenital disorder of glycosylation type Ia (CDG) (Matthijs et al. 1997. PubMed ID: 9140401; Kjaergaard et al. 2001. PubMed ID: 11517108; Andreotti et al. 2013. PubMed ID: 24498599). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD and interpreted as pathogenic in ClinVar by multiple independent submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/7711). This variant is interpreted as pathogenic.