ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.338C>T (p.Pro113Leu) (rs80338700)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790784 SCV000230063 pathogenic not provided 2016-04-19 criteria provided, single submitter clinical testing
Invitae RCV000008162 SCV000757675 pathogenic Congenital disorder of glycosylation, type Ia 2017-08-08 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 113 of the PMM2 protein (p.Pro113Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs80338700, ExAC 0.01%). This variant has been reported in many individuals affected with PMM2-related congenital disorder of glycosylation (PMM2-CDG, also known as CDG type Ia) (PMID: 9140401, 18948042, 21541725) and is one of the most common variants found in individuals with this disease (PMID: 11058895). ClinVar contains an entry for this variant (Variation ID: 7723). Experimental studies have shown that this missense change results in a shorter protein half-life, disrupts protein oligomerization, and results in reduced or absent enzyme activity in vitro and in cells derived from affected individuals (PMID: 9140401, 18948042, 21541725, 26014514). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000008162 SCV000915735 pathogenic Congenital disorder of glycosylation, type Ia 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.
OMIM RCV000008162 SCV000028367 pathogenic Congenital disorder of glycosylation, type Ia 2001-12-01 no assertion criteria provided literature only
GeneReviews RCV000008162 SCV000040581 pathologic Congenital disorder of glycosylation, type Ia 2011-04-21 no assertion criteria provided curation Converted during submission to Pathogenic.
Counsyl RCV000008162 SCV000678119 pathogenic Congenital disorder of glycosylation, type Ia 2015-06-06 no assertion criteria provided clinical testing
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

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