ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.66+1G>T (rs937726878)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780612 SCV000918028 likely pathogenic Congenital disorder of glycosylation, type Ia 2020-09-17 criteria provided, single submitter clinical testing Variant summary: PMM2 c.66+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.4e-05 in 219708 control chromosomes (gnomAD). c.66+1G>T has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation Type 1a (Le Bizec_2005, Leticee_2010, Monin_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000780612 SCV000992590 likely pathogenic Congenital disorder of glycosylation, type Ia 2019-07-03 criteria provided, single submitter research
Invitae RCV000780612 SCV001200999 pathogenic Congenital disorder of glycosylation, type Ia 2020-05-26 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 1 of the PMM2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with PMM2-congenital disorder of glycosylation (CDG-Ia) (PMID: 15844218, 20638314). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 632948). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMM2 are known to be pathogenic (PMID: 19862844). For these reasons, this variant has been classified as Pathogenic.

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