ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.357C>A (p.Phe119Leu) (rs80338701)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624449 SCV000742672 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Baylor Genetics RCV000008150 SCV000807615 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found once in our laboratory in trans with a pathogenic variant in a 1-year-old female with global delays, severe hypotonia, coarse features, failure to thrive, brain abnormalities, esotropia, nystagmus, abnromal fat distribution, inverted nipples, transferrin studies consistent with CDG. Heterozygotes would be expected to be asymptomatic carriers.
Counsyl RCV000008150 SCV000678064 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2015-06-13 criteria provided, single submitter clinical testing
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000008150 SCV000236531 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2015-01-14 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000008150 SCV000733548 pathogenic Carbohydrate-deficient glycoprotein syndrome type I no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790706 SCV000230900 pathogenic not provided 2013-06-07 criteria provided, single submitter clinical testing
GeneReviews RCV000008150 SCV000040582 pathologic Carbohydrate-deficient glycoprotein syndrome type I 2011-04-21 no assertion criteria provided curation Converted during submission to Pathogenic.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000008150 SCV000743893 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2014-10-08 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000008150 SCV000745881 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2017-06-21 no assertion criteria provided clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000008150 SCV000399673 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 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.
Integrated Genetics/Laboratory Corporation of America RCV000008150 SCV000920013 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 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.
Invitae RCV000008150 SCV000833921 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-01-18 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 119 of the PMM2 protein (p.Phe119Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs80338701, ExAC 0.02%). This variant has been reported in multiple individuals affected with PMM2-CDG (CDG-Ia) (PMID: 9140401, 15645285, 11517108, 9781039, 10801058). ClinVar contains an entry for this variant (Variation ID: 7711). Experimental studies have shown that this missense change decreases protein stability in vitro and in vivo (PMID: 26488408, 24498599) and the F119L/R141H genotype mimics human disease in mouse model (PMID: 27053713). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000008150 SCV000028355 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 1998-07-01 no assertion criteria provided literature only
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000008150 SCV000680023 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 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.

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