Submissions for variant NM_000303.3(PMM2):c.337C>A (p.Pro113Thr)

dbSNP: rs765433263

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482436	SCV000569753	likely pathogenic	not provided	2024-07-12	criteria provided, single submitter	clinical testing	Identified with a second variant in PMM2 in a patient in published literature; detailed clinical information and segregation was not reported (PMID: 37224763); 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: 37224763)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000984293	SCV003491859	likely pathogenic	PMM2-congenital disorder of glycosylation	2023-02-14	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 113 of the PMM2 protein (p.Pro113Thr). This variant is present in population databases (rs765433263, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PMM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 420784). 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. This variant disrupts the p.Pro113 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9140401, 11058895, 18948042, 21541725). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Counsyl	RCV000984293	SCV001132462	uncertain significance	PMM2-congenital disorder of glycosylation	2019-01-24	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004755929	SCV005342091	likely pathogenic	PMM2-related disorder	2024-09-05	no assertion criteria provided	clinical testing	The PMM2 c.337C>A variant is predicted to result in the amino acid substitution p.Pro113Thr. This variant has been reported in the presumed compound heterozygous state with a PMM2 nonsense variant (c.109C>T, p.Gln37*) in an individual with congenital disorder of glycosylation type 1a (PMM2-CDG) (Table 2, De Graef et al. 2023. PubMed ID: 37224763). This variant is reported in 0.0029% of alleles (1 of 34,590) in individuals of Latino descent in gnomAD. Of note, another missense variant affecting the same amino acid residue (p.Pro113Leu) has been reported in multiple individuals with PMM2-CDG and shown to cause a loss of function (Matthijs et al. 1997. PubMed ID: 9140401; Vega et al. 2011. PubMed ID: 21541725; Yuste-Checa et al. 2015. PubMed ID: 26014514; Segovia-Falquina et al. 2022. PubMed ID: 35789514). Taken together, the p.Pro113Thr variant is interpreted as likely pathogenic.