ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.640-9T>G (rs370160676)

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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 RCV000780609 SCV000918025 pathogenic Congenital disorder of glycosylation, type Ia 2018-08-10 criteria provided, single submitter clinical testing Variant summary: PMM2 c.640-9T>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Five predict the variant weakens a 3 acceptor site. The splice impact of the variant was confirmed by a functional study (Vega_2008). The variant allele was found at a frequency of 1.2e-05 in 245852 control chromosomes. c.640-9T>G has been reported in the literature in individuals affected with Congenital Disorder of Glycosylation Type 1a. These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000780609 SCV001163406 pathogenic Congenital disorder of glycosylation, type Ia criteria provided, single submitter clinical testing
Invitae RCV000780609 SCV001387044 likely pathogenic Congenital disorder of glycosylation, type Ia 2020-05-05 criteria provided, single submitter clinical testing This sequence change falls in intron 7 of the PMM2 gene. It does not directly change the encoded amino acid sequence of the PMM2 protein. This variant is present in population databases (rs370160676, ExAC 0.003%). This variant has been observed in individual(s) with congenital disorder of glycosylation type 1a (PMID: 19235233). 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: 621848). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 19235233). 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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