ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.710C>T (p.Thr237Met) (rs80338708)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000020237 SCV000221115 likely pathogenic Congenital disorder of glycosylation, type Ia 2015-02-06 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000514240 SCV000232513 pathogenic not provided 2017-05-13 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000514240 SCV000609595 pathogenic not provided 2017-08-24 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000020237 SCV000611239 pathogenic Congenital disorder of glycosylation, type Ia 2017-05-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000623731 SCV000742595 pathogenic Inborn genetic diseases 2017-07-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Invitae RCV000020237 SCV000757674 pathogenic Congenital disorder of glycosylation, type Ia 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 237 of the PMM2 protein (p.Thr237Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs80338708, ExAC 0.01%). This variant has been reported in combination with another PMM2 variant in individuals affected with congenital disorder of glycosylation type 1 (PMID: 11891694, 11589167, 23430838, 23988505, 21541725). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in one of these individuals which is consistent with autosomal recessive inheritance and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 21145). Experimental studies have shown that this missense change causes a significant reduction in PMM2 activity and destabilizes the protein (PMID: 21541725, 26014514). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000514240 SCV001248283 pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000020237 SCV001337988 pathogenic Congenital disorder of glycosylation, type Ia 2020-01-27 criteria provided, single submitter clinical testing Variant summary: PMM2 c.710C>T (p.Thr237Met) 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 4.4e-05 in 251084 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PMM2 causing Congenital Disorder of Glycosylation Type 1a (4.4e-05 vs 0.0056), allowing no conclusion about variant significance. c.710C>T has been reported in the literature in multiple individuals affected with Congenital Disorder of Glycosylation Type 1a (example, Matthijs_1997, Briones_2001, Tayebi_2002, Bortot_2013, Vega_2011). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity due to a destabilizing outcome on folding (example Vega_2011 and Yuste-Checa_2015). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=5)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews RCV000020237 SCV000040590 pathologic Congenital disorder of glycosylation, type Ia 2011-04-21 no assertion criteria provided curation Converted during submission to Pathogenic.

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