ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs937726878
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Total submissions: 5
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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 PMM2-congenital disorder of glycosylation 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 PMM2-congenital disorder of glycosylation 2019-07-03 criteria provided, single submitter research
Invitae RCV000780612 SCV001200999 pathogenic PMM2-congenital disorder of glycosylation 2023-12-25 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. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMM2 are known to be pathogenic (PMID: 19862844). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site 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 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. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000780612 SCV002813930 likely pathogenic PMM2-congenital disorder of glycosylation 2022-03-18 criteria provided, single submitter clinical testing
Baylor Genetics RCV000780612 SCV004205314 pathogenic PMM2-congenital disorder of glycosylation 2022-08-30 criteria provided, single submitter clinical testing

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