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

dbSNP: rs80338708

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000020237	SCV000221115	likely pathogenic	PMM2-congenital disorder of glycosylation	2015-02-06	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	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	PMM2-congenital disorder of glycosylation	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000020237	SCV000757674	pathogenic	PMM2-congenital disorder of glycosylation	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 237 of the PMM2 protein (p.Thr237Met). This variant is present in population databases (rs80338708, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1 (PMID: 11589167, 11891694, 21541725, 23430838, 23988505). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 21145). 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: 21541725, 26014514). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000514240	SCV001248283	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PMM2: PM3:Very Strong, PM2, PM5, PP4:Moderate, PS3:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020237	SCV001337988	pathogenic	PMM2-congenital disorder of glycosylation	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.
Diagnostic Laboratory, Strasbourg University Hospital	RCV001257700	SCV001434511	pathogenic	Intellectual disability	2020-04-20	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000514240	SCV001712855	pathogenic	not provided	2020-05-21	criteria provided, single submitter	clinical testing	PS3, PS4, PM2, PM3, PM5, PP3, PP4, PP5
GeneDx	RCV000514240	SCV001811583	pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a reduced residual activity in T237M when compared with wild type, and T237M was identified as destabilizing variant (Vega et al., 2011; Yuste-Checa et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); 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: 10801058, 28685491, 11589167, 21541725, 9140401, 23988505, 11891694, 26014514, 15844218, 11156536, 11058895, 27774737, 19235233, 28425223, 12705494, 31736265, 33413482)
Revvity Omics, Revvity	RCV000020237	SCV002018866	pathogenic	PMM2-congenital disorder of glycosylation	2023-10-26	criteria provided, single submitter	clinical testing
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV000020237	SCV002574831	pathogenic	PMM2-congenital disorder of glycosylation	2022-09-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000020237	SCV004204831	pathogenic	PMM2-congenital disorder of glycosylation	2024-02-22	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000020237	SCV005200486	pathogenic	PMM2-congenital disorder of glycosylation		criteria provided, single submitter	clinical testing	The variant c.710C>T has been reported in a homozygous state in similarly affected individuals with congenital disorder of glycosylation, type Ia earlier (Matthijs et al., 1997). This variant was also reported in the ClinVar database as a likely pathogenic/pathogenic variant in 17 independent submissions (ClinVar ID: 21145). In silico prediction tools (MutationTaster, CADD phred, and REVEL) are consistent in predicting the variant to be damaging to PMM2 protein function.
GeneReviews	RCV000020237	SCV000040590	not provided	PMM2-congenital disorder of glycosylation		no assertion provided	literature only
Natera, Inc.	RCV000020237	SCV002092453	pathogenic	PMM2-congenital disorder of glycosylation	2017-09-23	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407349	SCV004114579	pathogenic	PMM2-related disorder	2024-09-19	no assertion criteria provided	clinical testing	The PMM2 c.710C>T variant is predicted to result in the amino acid substitution p.Thr237Met. This variant has been documented as causative for autosomal recessive congenital disorder of glycosylation type Ia when present with a second causative variant (Matthijs et al. 1997. PubMed ID: 9140401; Tayebi et al. 2002. PubMed ID: 11891694; Bortot et al. 2013. PubMed ID: 23988505). Functional studies have shown that the p.Thr237Met substitution causes a partial decrease in protein abundance and residual enzymatic activity, and the authors suggest a mild classification for this variant (Vega et al. 2011. PubMed ID: 21541725; Yuste-Checa et al. 2015. PubMed ID: 26014514). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD. Given the evidence, we interpret c.710C>T (p.Thr237Met) as pathogenic.