ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.722G>C (p.Cys241Ser) (rs80338709)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623621 SCV000741806 pathogenic Inborn genetic diseases 2016-09-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000153745 SCV000610219 pathogenic not provided 2017-04-25 criteria provided, single submitter clinical testing
Counsyl RCV000008156 SCV000487108 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2016-10-12 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000153745 SCV000232518 pathogenic not provided 2014-01-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000008156 SCV000894097 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-10-31 criteria provided, single submitter clinical testing
GeneReviews RCV000008156 SCV000040591 pathologic Carbohydrate-deficient glycoprotein syndrome type I 2011-04-21 no assertion criteria provided curation Converted during submission to Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000008156 SCV000696504 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2017-06-26 criteria provided, single submitter clinical testing Variant summary: The PMM2 c.722G>C (p.Cys241Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 9/120396 control chromosomes at a frequency of 0.0000748, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMM2 variant (0.0055902). The variant has been reported in numerous CDG1A patients and has been associated with a mild phenotype. Patient fibroblasts (which also carry a second pathogenic variant) show ~30% residual enzyme activity, and functional studies using expression systems also show <30% residual enzyme activity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000008156 SCV000633728 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 241 of the PMM2 protein (p.Cys241Ser). The cysteine residue is moderately conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is present in population databases (rs80338709, ExAC 0.06%). This variant is a common cause of mild congenital disorder of glycosylation Ia (CDG-Ia). It has been reported as compound heterozygous in multiple affected individuals with evidence of segregation with disease within families (PMID: 21541725, 25355454, 15844218, 11715002, 11156536). Fibroblasts from individuals carrying this variant show residual PMM2 activities of 5-31% (PMID: 21541725). ClinVar contains an entry for this variant (Variation ID: 7717). Experimental studies have shown that this missense change impairs PMM2 protein function and results in an enzyme with residual activity in vitro (PMID: 11715002, 21541725, 22012410, 26014514). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000008156 SCV000028361 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2001-02-01 no assertion criteria provided literature only

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