Submissions for variant NM_000303.3(PMM2):c.484C>T (p.Arg162Trp)

gnomAD frequency: 0.00002  dbSNP: rs104894526

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000008148	SCV000220327	likely pathogenic	PMM2-congenital disorder of glycosylation	2014-05-16	criteria provided, single submitter	literature only
GeneDx	RCV000403363	SCV000329703	pathogenic	not provided	2022-01-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the variant protein is less stable and has reduced enzyme activity compared to the wild-type protein (Yuste-Checa et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26502900, 23430838, 26014514, 9140401, 30406445, 17166182, 10386614, 10527672, 15844218, 18948042, 11156536, 21541725, 32222543, 31589614, 33643843)
SIB Swiss Institute of Bioinformatics	RCV000008148	SCV000803453	likely pathogenic	PMM2-congenital disorder of glycosylation	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Likely Pathogenic, for Congenital disorder of glycosylation, type Ia, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:21541725). PS3 => Well-established functional studies show a deleterious effect (PMID:21541725,10386614).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000008148	SCV000829571	pathogenic	PMM2-congenital disorder of glycosylation	2024-03-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 162 of the PMM2 protein (p.Arg162Trp). This variant is present in population databases (rs104894526, gnomAD 0.006%). This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1a (PMID: 9140401, 9497260, 15844218, 17166182, 21541725). 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: 7709). 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 80%. Experimental studies have shown that this missense change affects PMM2 function (PMID: 10386614, 26014514). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000403363	SCV001247656	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000008148	SCV002026349	pathogenic	PMM2-congenital disorder of glycosylation	2021-10-29	criteria provided, single submitter	clinical testing	This variant was identified heterozygous with NM_000303.3:c.47C>T._x000D_ Criteria applied: PM3_VSTR, PS3_MOD, PM2_SUP, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000008148	SCV002074201	pathogenic	PMM2-congenital disorder of glycosylation	2022-01-11	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.484C>T (p.Arg162Trp) results in a non-conservative amino acid change located in the Cap domain (Yuste-Checa_2015) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251394 control chromosomes (gnomAD). c.484C>T has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation (Matthijs_19997, Yang_2018, Quelhas2020, Lipiski_2021). These data indicate that the variant is very likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and this variant effect results in reducing enzyme activity (Pirard_19999, Yuste-Checa_2015). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=5) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
DASA	RCV000008148	SCV002107085	pathogenic	PMM2-congenital disorder of glycosylation	2022-03-05	criteria provided, single submitter	clinical testing	The c.484C>T;p.(Arg162Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 7709; PMID: 9140401; PMID: 17166182; PMID: 9497260; PMID: 21541725; PMID: 15844218) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (PMM) - PM1. The variant is present at low allele frequencies population databases (rs104894526 – gnomAD 0.0001591%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000008148	SCV002557195	pathogenic	PMM2-congenital disorder of glycosylation	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with type Ia congenital disorder of glycosylation (MIM#212065). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to trypophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0309 An alternative amino acid change at the same position has been observed in gnomAD (v2) (highest allele frequency: 7 heterozygotes, 0 homozygote). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated PMM functional domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with congenital disorder of glycosylation (ClinVar, Decipher, PMID: 9140401, 28915903, 30406445). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional assessment of the variant showed decreased dimerisation, stability and enzymatic activity (PMID: 26014514) (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000008148	SCV002810328	pathogenic	PMM2-congenital disorder of glycosylation	2024-03-27	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000008148	SCV003807984	pathogenic	PMM2-congenital disorder of glycosylation	2022-10-31	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PM2 supporting, PM3 very strong, PP3 supporting
3billion, Medical Genetics	RCV000008148	SCV004013626	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: 0.002%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10386614, 26014514). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.70; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007709 / PMID: 9140401). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 21541725). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000008148	SCV004205282	pathogenic	PMM2-congenital disorder of glycosylation	2024-02-28	criteria provided, single submitter	clinical testing
OMIM	RCV000008148	SCV000028353	pathogenic	PMM2-congenital disorder of glycosylation	1997-05-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000008148	SCV001457177	pathogenic	PMM2-congenital disorder of glycosylation	2020-09-16	no assertion criteria provided	clinical testing