ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.470T>C (p.Phe157Ser) (rs190521996)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169083 SCV000220257 likely pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2014-04-21 criteria provided, single submitter literature only
Fulgent Genetics,Fulgent Genetics RCV000169083 SCV000894092 likely pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000481553 SCV000568193 pathogenic not provided 2018-12-11 criteria provided, single submitter clinical testing The F157S variant in the PMM2 gene has been reported previously in association with CDG-1a, with clinical features of affected individuals ranging from mild to severe (Romano et al., 2009; Grunewald et al., 2001; Resende et al., 2014). The F157S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F157S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies showed that F157S was associated with undetectable phosphomannomutase function (Romano et al., 2009). We interpret F157S as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000169083 SCV000399675 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2017-04-27 criteria provided, single submitter clinical testing Across a selection of the available literature, the PMM2 c.470T>C (p.Phe157Ser) missense variant is reported in a compound heterozygous state with a second variant in eight patients with congenital disorder of glycosylation type 1a (CDG1a), and in one patient where zygosity information is not provided (Matthijs et al. 1999; Briones et al. 2002; Noelle et al. 2005; Romano et al. 2009; Vega et al. 2011; Casado et al. 2012; Resende et al. 2014). Nearly all of these patients exhibited a severe phenotype and residual PMM2 enzyme activity in patient fibroblasts was extremely low or undetectable. Control data are unavailable for this variant, which is reported at a frequency of 0.00081 in the European American population of the Exome Sequencing Project. Analysis of the p.Phe157Ser variant in a prokaryotic expression system showed that the variant affected the stability and structure, and significantly decreased the half-life of the protein (Vega et al. 2011). Based on the collective evidence, the p.Phe157Ser 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.
Integrated Genetics/Laboratory Corporation of America RCV000169083 SCV000696500 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2016-06-03 criteria provided, single submitter clinical testing Variant summary: The PMM2 c.470T>C (p.Phe157Ser) variant causes a missense mutation involving a conserved nucleotide with 5/5 in silico tools predicting a damaging outcome, which functional studies support this prediction. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 33/121274 (1/3675), which does not exceed the estimated maximal expected allele frequency for a pathogenic PMM2 variant of 1/178. (0.0055902). The variant of interest has been reported in multiple affected individuals via publications, along with a reputable clinical laboratory citing the variant as "likely pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic.
Invitae RCV000169083 SCV000757672 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 157 of the PMM2 protein (p.Phe157Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is present in population databases (rs190521996, ExAC 0.05%). This variant has been reported in combination with another PMM2 variant in several individuals affected with congenital disorder of glycosylation type Ia (PMID: 24739649, 11156536, 22012410, 21541725, 19357119, 25355454, 15645285). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 188763). Experimental studies have shown that this missense change reduces protein stability and abrogates PMM2 activity (PMID: 21541725). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000169083 SCV000680022 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2017-07-05 criteria provided, single submitter clinical testing The NM_000303.2(PMM2):c.470T>C missense variant was identified in exon 6 of the PMM2 gene. This substitution creates a major amino acid change from a phenylalanine to a serine at position 157, NP_000294.1(PMM2):p.(Phe157Ser). 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 present in the gnomAD population database at a frequency of 0.03%. It is situated in a phosphomannomutase (PMM) domain. It has been previously reported in patients with congenital disorder of glycosylation (ClinVar). In addition, functional studies show this variant in compound heterozygous state affects structural stability and reduces enzyme activity (Noelle et al., (2005) and Vega et al., (2011)). Based on current information and in association with the NM_000303.2(PMM2):c.357C>A missense variant, this variant has been classified as PATHOGENIC.

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