Submissions for variant NM_000303.3(PMM2):c.634A>G (p.Met212Val)

gnomAD frequency: 0.00014  dbSNP: rs3743808

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780610	SCV000918026	benign	not specified	2021-08-24	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.634A>G (p.Met212Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 396268 control chromosomes, predominantly at a frequency of 0.0086 within the East Asian subpopulation in the gnomAD database (v2.1 and v3.1 datasets), including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.54 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMM2 causing Congenital Disorder of Glycosylation Type 1a phenotype (0.0056). However, the variant was reported in some East Asian subpopulations with an even higher allele frequency, e.g. in the Japanese, with an allele frequency of 0.026 (in the jMorp database). This frequency is about 4.6-fold higher than the maximum expected for a pathogenic variant, strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Though the variant, c.634A>G, has been reported in the literature in an East Asian individual affected with Congenital Disorder of Glycosylation Type 1a (Ren_2015), this report does not provide unequivocal conclusions about association of the variant with Congenital Disorder of Glycosylation Type 1a. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, while the other laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV000877159	SCV001019851	likely benign	PMM2-congenital disorder of glycosylation	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000877159	SCV001274416	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genetic Services Laboratory, University of Chicago	RCV000780610	SCV002070549	likely benign	not specified	2018-12-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000877159	SCV003811203	uncertain significance	PMM2-congenital disorder of glycosylation	2021-12-02	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000877159	SCV002089492	likely benign	PMM2-congenital disorder of glycosylation	2020-01-16	no assertion criteria provided	clinical testing