ClinVar Genomic variation as it relates to human health

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)

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.

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

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."

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.

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.

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP3,PP5.

ACMG classification criteria: PS3, PS4, PM2, PM3, PP2

PS4, PM1, PM2, PM5, PP2, PP3, PP5

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.

The PMM2 c.710C>G variant is predicted to result in the amino acid substitution p.Thr237Arg. This variant was reported in the compound heterozygous state in multiple individuals with congenital disorder of glycosylation 1a (Matthijs et al. 1998. PubMed ID: 9497260; Aronica et al. 2005. PubMed ID: 15714316; Starosta et al. 2021. PubMed ID: 33413482; Le Bizec et al. 2005. PubMed ID: 15844218; Barone et al. 2014. PubMed ID: 25355454). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.