Submissions for variant NM_000303.3(PMM2):c.421C>T (p.Arg141Cys)

gnomAD frequency: 0.00004  dbSNP: rs746610168

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665622	SCV000789774	likely pathogenic	PMM2-congenital disorder of glycosylation	2017-02-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000665622	SCV000944707	likely pathogenic	PMM2-congenital disorder of glycosylation	2023-10-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 141 of the PMM2 protein (p.Arg141Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with congenital disorder of glycosylation (PMID: 15844218). ClinVar contains an entry for this variant (Variation ID: 550780). 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. Experimental studies have shown that this missense change affects PMM2 function (PMID: 15844218). This variant disrupts the p.Arg141 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9497260, 11517108, 19357119, 21541725, 25355454). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000665622	SCV001338378	likely pathogenic	PMM2-congenital disorder of glycosylation	2020-02-21	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.421C>T (p.Arg141Cys) 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 2.1e-05 in 193568 control chromosomes (gnomAD). c.421C>T has been reported in the literature in a family affected with Congenital Disorder of Glycosylation Type 1a (LeBizec_2005). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in an E. coli-based expression system (LeBizec_2005). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV002286774	SCV002577223	pathogenic	not provided	2022-03-14	criteria provided, single submitter	clinical testing	Reported in a patient with Congenital disorder of Glycosylation type Ia who also harbored an additional missense variant in the PMM2 gene (Le Bizec et al., 2005); 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; Published functional studies demonstrate that this variant has a damaging effect on the function of the PMM2 protein (Le Bizec et al., 2005); This variant is associated with the following publications: (PMID: 11058895, 26206375, 16540464, 15844218)
Fulgent Genetics, Fulgent Genetics	RCV000665622	SCV002810489	likely pathogenic	PMM2-congenital disorder of glycosylation	2021-09-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002532044	SCV003528953	uncertain significance	Inborn genetic diseases	2022-12-21	criteria provided, single submitter	clinical testing	The c.421C>T (p.R141C) alteration is located in exon 5 (coding exon 5) of the PMM2 gene. This alteration results from a C to T substitution at nucleotide position 421, causing the arginine (R) at amino acid position 141 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV000665622	SCV004204836	likely pathogenic	PMM2-congenital disorder of glycosylation	2023-12-23	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000665622	SCV001457173	likely pathogenic	PMM2-congenital disorder of glycosylation	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004756003	SCV005354750	likely pathogenic	PMM2-related disorder	2024-09-24	no assertion criteria provided	clinical testing	The PMM2 c.421C>T variant is predicted to result in the amino acid substitution p.Arg141Cys. This variant along with a second variant in this gene has been reported in one family with congenital disorder of glycosylation 1a (Le Bizec et al. 2005. PubMed ID: 15844218). A different variant affecting the same amino acid (p.Arg141His) has been reported to be the most common disease allele for carbohydrate-deficient-glycoprotein syndrome type 1 (Matthijs et al. 1998. PubMed ID: 9497260). This variant is reported in 0.0048% of alleles in individuals of African descent in gnomAD. In ClinVar, this variant has been reported as likely pathogenic/pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/550780/). This variant is interpreted as likely pathogenic.