ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.710C>G (p.Thr237Arg) (rs80338708)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000008155 SCV000678067 likely pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2014-01-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790820 SCV000232519 pathogenic not provided 2013-04-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000008155 SCV000894096 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000008155 SCV000399682 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2017-04-27 criteria provided, single submitter clinical testing The PMM2 c.710C>G (p.Thr237Arg) missense variant has been reported in at least six studies in which it is found in a total of nine patients with congenital disorders of glycosylation type 1a, all of whom were in a compound heterozygous state with either one or two other missense variants (Matthijs et al. 1998; Kjaergaard et al. 1999; Grünewald et al. 2001; Aronica et al. 2005; Le Bizec et al. 2005; García-López et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00027 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in E.coli showed that the variant protein was produced in similar quantities compared to wild type and was present in the same subcellular fraction but had no detectable catalytic activity (Kjaergaard et al. 1999). Based on the collective evidence, the p.Thr237Arg variant is classified as pathogenic 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 RCV000008155 SCV000696503 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2016-09-09 criteria provided, single submitter clinical testing Variant summary: The PMM2 c.710C>G (p.Thr237Arg) variant causes a missense change involving a conserved nucleotide with 5/5 in silico tools predicting a "damaging" outcome, which PMM2 activity detection levels support this. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 18/120616 (1/6702), which does not exceed the estimated maximal expected allele frequency for a pathogenic PMM2 variant of 1/178. Multiple publications report the variant in compound heterozygote and homozygote affected individuals. In addition, multiple reputable databases and clinical diagnostic laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic."
Invitae RCV000008155 SCV000958650 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces threonine with arginine at codon 237 of the PMM2 protein (p.Thr237Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is present in population databases (rs80338708, ExAC 0.03%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant or in combination with PMM2 variants in several individuals affected with PMM2-CDG (PMID: 9497260, 10602363, 15714316, 25355454, 25497157). 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: 7716). Experimental studies have shown that this missense change abrogates PMM2 enzymatic activity in vitro (PMID: 10602363). Variants that disrupt the p.Thr237 amino acid residue in PMM2 have been observed in affected individuals (PMID: 11156536, 9497260, 15714316 11891694, 11589167). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000008155 SCV000028360 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 1999-12-01 no assertion criteria provided literature only

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