ClinVar Miner

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

dbSNP: rs80338708
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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000790820 SCV000232519 pathogenic not provided 2013-04-03 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000008155 SCV000399682 pathogenic PMM2-congenital disorder of glycosylation 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000008155 SCV000696503 pathogenic PMM2-congenital disorder of glycosylation 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."
Fulgent Genetics, Fulgent Genetics RCV000008155 SCV000894096 pathogenic PMM2-congenital disorder of glycosylation 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000008155 SCV000958650 pathogenic PMM2-congenital disorder of glycosylation 2024-01-25 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 237 of the PMM2 protein (p.Thr237Arg). This variant is present in population databases (rs80338708, gnomAD 0.03%). This missense change has been observed in individuals with PMM2-CDG (PMID: 9497260, 10602363, 15714316, 25355454, 25497157). ClinVar contains an entry for this variant (Variation ID: 7716). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMM2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PMM2 function (PMID: 10602363). This variant disrupts the p.Thr237 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9497260, 11156536, 11589167, 11891694, 15714316). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Pediatric Metabolic Diseases, Hacettepe University RCV000008155 SCV000998572 pathogenic PMM2-congenital disorder of glycosylation criteria provided, single submitter clinical testing
Baylor Genetics RCV000008155 SCV001163407 pathogenic PMM2-congenital disorder of glycosylation criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000008155 SCV001194151 likely pathogenic PMM2-congenital disorder of glycosylation 2020-01-06 criteria provided, single submitter clinical testing NM_000303.2(PMM2):c.710C>G(T237R) is classified as likely pathogenic in the context of congenital disorder of glycosylation type Ia. Sources cited for classification include the following: PMID 10602363, 17920054, 25355454 and 11058895. Classification of NM_000303.2(PMM2):c.710C>G(T237R) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000008155 SCV001366369 pathogenic PMM2-congenital disorder of glycosylation 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP3,PP5.
Molecular Biology Laboratory, Fundació Puigvert RCV000008155 SCV001425247 likely pathogenic PMM2-congenital disorder of glycosylation 2020-02-01 criteria provided, single submitter research
GeneDx RCV000790820 SCV001797055 pathogenic not provided 2021-11-11 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect (Kjaergaard et al., 1999); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9497260, 15714316, 11058896, 15844218, 1058895, 11156536, 20638314, 23988505, 10602363, 32304219, 31980526, 33532864, 33413482, 11409861, 34426522, 31589614, 33643843)
Revvity Omics, Revvity RCV000008155 SCV002018865 pathogenic PMM2-congenital disorder of glycosylation 2021-06-24 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002251889 SCV002523658 pathogenic See cases 2020-04-17 criteria provided, single submitter clinical testing ACMG classification criteria: PS3, PS4, PM2, PM3, PP2
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000008155 SCV002577413 pathogenic PMM2-congenital disorder of glycosylation 2022-06-28 criteria provided, single submitter clinical testing PS4, PM1, PM2, PM5, PP2, PP3, PP5
Ambry Genetics RCV002512893 SCV003737587 pathogenic Inborn genetic diseases 2021-10-09 criteria provided, single submitter clinical testing The c.710C>G (p.T237R) alteration is located in exon 8 (coding exon 8) of the PMM2 gene. This alteration results from a C to G substitution at nucleotide position 710, causing the threonine (T) at amino acid position 237 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of 0.01% (39/282470) total alleles studied. The highest observed frequency was 0.03% (38/129066) of European (non-Finnish) alleles. This alteration has been reported presumably in trans with another PMM2 alteration in several unrelated individuals with congenital disorder of glycosylation type 1a (Matthijs, 1998; Kjaergaard, 1999; Le Bizec, 2005; Monin, 2014; Barone, 2015; García-López, 2016). In addition, another alteration at this position (p.T237M) has also been reported (Matthijs, 1997; Vega, 2011). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies of the p.T237R variant in E.coli showed no measurable residual PMM2 activity (Kjaergaard, 1999). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
3billion RCV000008155 SCV004013625 pathogenic PMM2-congenital disorder of glycosylation criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10602363). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.92). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007716 / PMID: 9497260). Different missense changes at the same codon (p.Thr237Lys, p.Thr237Met) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000021145 / PMID: 28139241, 9140401). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000790820 SCV004242672 pathogenic not provided 2024-02-06 criteria provided, single submitter clinical testing
OMIM RCV000008155 SCV000028360 pathogenic PMM2-congenital disorder of glycosylation 1999-12-01 no assertion criteria provided literature only
Clinical Genetics, Academic Medical Center RCV000790820 SCV001917102 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000790820 SCV001930336 likely pathogenic not provided no assertion criteria provided clinical testing
Natera, Inc. RCV000008155 SCV002092452 pathogenic PMM2-congenital disorder of glycosylation 2017-09-23 no assertion criteria provided clinical testing

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