ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.634A>G (p.Met212Val) (rs3743808)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000780610 SCV000918026 likely benign not specified 2020-07-09 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 0.00068 in 251478 control chromosomes, predominantly at a frequency of 0.0087 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.6-fold of the estimated maximal expected allele frequency (MPAF) 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 other 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 likely benign.
Invitae RCV000877159 SCV001019851 likely benign Congenital disorder of glycosylation, type Ia 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000877159 SCV001274416 uncertain significance Congenital disorder of glycosylation, type Ia 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.

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