ClinVar Miner

Submissions for variant NM_015599.3(PGM3):c.1474C>T (p.Arg492Ter)

gnomAD frequency: 0.00001  dbSNP: rs144104577
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000613688 SCV000713007 likely pathogenic Immunodeficiency 23 2017-04-06 criteria provided, single submitter clinical testing The p.Arg520X variant in PGM3 has not been previously reported in individuals wi th immunodeficiency, but has been identified in 4/66736 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 144104577). This nonsense variant leads to a premature termination codon at posi tion 520, which is predicted to lead to a truncated or absent protein. Bialleli c variants in the PGM3 gene that result in reduced PGM3 expression and/or enzyma tic function are reported to cause autosomal recessive immunodeficiency 23 (MIM: 615816). In summary, although additional studies are required to fully establi sh its clinical significance, the p.Arg520X variant is likely pathogenic.
Invitae RCV000613688 SCV000933408 pathogenic Immunodeficiency 23 2024-01-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg520*) in the PGM3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PGM3 are known to be pathogenic (PMID: 17548465, 24589341, 24931394). This variant is present in population databases (rs144104577, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with PGM3-congenital disorder of glycosylation (PMID: 35040011). ClinVar contains an entry for this variant (Variation ID: 505650). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity Omics RCV000613688 SCV002018773 pathogenic Immunodeficiency 23 2020-05-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003226337 SCV003922801 likely pathogenic Severe combined immunodeficiency disease 2023-03-28 criteria provided, single submitter clinical testing Variant summary: PGM3 c.1558C>T (p.Arg520X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.8e-05 in 251408 control chromosomes (gnomAD). c.1558C>T has been reported in the literature in at least one compound heterozygous individual affected with Severe Combined Immunodeficiency (Winslow_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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