ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.447+5G>A

gnomAD frequency: 0.00002  dbSNP: rs367852554
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487388 SCV000565887 likely pathogenic not provided 2018-12-13 criteria provided, single submitter clinical testing The c.447+5 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. This variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Several in-silico splice prediction models predict that c.447+5 G>A destroys the canonical splice donor site in intron 5. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, c.447+5 G>A is a strong candidate for a pathogenic variant, however the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp RCV002525778 SCV003521406 uncertain significance PMM2-congenital disorder of glycosylation 2022-07-08 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the PMM2 gene. It does not directly change the encoded amino acid sequence of the PMM2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs367852554, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PMM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 418663). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000487388 SCV003932201 uncertain significance not provided 2023-03-10 criteria provided, single submitter clinical testing PM2, PP3

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