ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.255+1G>A (rs1060499598)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477824 SCV000536849 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2016-02-17 no assertion criteria provided research
Fulgent Genetics,Fulgent Genetics RCV000477824 SCV000894090 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000477824 SCV000920016 likely pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-05-21 criteria provided, single submitter clinical testing Variant summary: PMM2 c.255+1G>A 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: Five 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 1.2e-05 in 246154 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PMM2 causing Congenital Disorder of Glycosylation Type 1a (1.2e-05 vs 0.0056), allowing no conclusion about variant significance. c.255+1G>A has been reported in the literature in at least one individual affected with Congenital Disorder of Glycosylation Type 1a. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000477824 SCV000757676 likely pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2017-10-19 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 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 reported in combination with another PMM2 variant in an individual affected with congenital disorder of glycosylation I (PMID: 15844218). ClinVar contains an entry for this variant (Variation ID: 417920). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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