Submissions for variant NM_000303.3(PMM2):c.713G>A (p.Arg238His)

gnomAD frequency: 0.00035  dbSNP: rs151319324

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000513790	SCV000232517	uncertain significance	not provided	2015-08-24	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513790	SCV000610857	uncertain significance	not provided	2017-08-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000555818	SCV000633727	likely benign	PMM2-congenital disorder of glycosylation	2025-01-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000555818	SCV000896577	uncertain significance	PMM2-congenital disorder of glycosylation	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000555818	SCV001274419	uncertain significance	PMM2-congenital disorder of glycosylation	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000513790	SCV001983792	uncertain significance	not provided	2024-03-07	criteria provided, single submitter	clinical testing	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, 37372416, 25681648, 10066032, 27231023, 36099812, 34652821, 37224763, 34132027)
Morava/Kozicz Lab, Department of Clinical Genomics, Mayo Clinic	RCV000555818	SCV002106368	likely pathogenic	PMM2-congenital disorder of glycosylation	2022-03-18	criteria provided, single submitter	clinical testing	Missense variants in nearby residues reported in the HGMD in individuals with PMM2-CD (Stenson et al, 2014) (PM1). Observed with pathogenic variant on the opposite allele (in trans) in this patient (PM3). Parents are heterozygotes. The mode of inheritance is in line with previous reports (AR). The majority of missense variants in this gene are considered pathogenic (Stenson et al 2014). In silico analysis, which includes protein predictors and evolutionary conservation supports a deleterious effect (PP3). Observed in 0.0549 % (155/282362 alleles) in large population cohorts (Lek et al, 2016). Phenotype of the patient is in line with previously described PMM2-CDG patients (PP4). Other clinical tests stronly support PMM2-CDG diagnosis and indicate the variant is pathogenic. According to the guidelines of ACMG we classify this variant as likely pathogenic (2 PM and 2 PP).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282006	SCV002572162	uncertain significance	not specified	2025-02-24	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.713G>A (p.Arg238His) results in a non-conservative amino acid change in 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 0.0004 in 1613530 control chromosomes, predominantly at a frequency of 0.0053 within the Ashkenazi Jewish subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in PMM2 causing Congenital Disorder of Glycosylation Type 1a (0.0004 vs 0.0056), allowing no conclusion about variant significance. c.713G>A has been reported in the literature in at least an individual affected with Congenital Disorder of Glycosylation Type 1a (Lam_2024). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27231023, 34132027, 34652821, 36099812, 37372416, 38959600). ClinVar contains an entry for this variant (Variation ID: 198714). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000555818	SCV005912563	uncertain significance	PMM2-congenital disorder of glycosylation	2023-08-29	criteria provided, single submitter	research
Natera, Inc.	RCV000555818	SCV001457771	likely benign	PMM2-congenital disorder of glycosylation	2020-04-17	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000513790	SCV001923445	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000513790	SCV001953757	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000513790	SCV001967421	uncertain significance	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Brain Gene Registry	RCV000555818	SCV003931144	not provided	PMM2-congenital disorder of glycosylation		no assertion provided	phenotyping only	Variant classified as Likely pathogenic and reported on 10-26-2020 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.