ClinVar Miner

Submissions for variant NM_015599.3(PGM3):c.965T>C (p.Ile322Thr) (rs745508510)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000554532 SCV000898869 uncertain significance Immunodeficiency 23 2018-04-30 criteria provided, single submitter clinical testing PGM3 NM_001199917.1 exon 9 p.Ile350Thr (c.1049T>C): This variant has been reported in the literature (as p.Ile322Thr) as homozygous in 1 individual with recurrent infection, neutropenia and eosinophilia, segregating with disease in 1 affected family member (Bjorksten 1976 PMID:1245758, Lundin 2015 PMID:26482871). Of note, both unaffected parents and an unaffected sibling were identified to be heterozygous; two other siblings were also affected but did not receive genetic testing. This variant is present in 2/111592 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs745508510). This variant is present in ClinVar (Variation ID:421723). Evolutionary conservation and computational predictive tools for this variant are unclear. In vitro functional studies suggest that this variant destabilizes the protein (Lundin 2015 PMID:26482871). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
GeneDx RCV000480499 SCV000571015 likely pathogenic not provided 2018-05-15 criteria provided, single submitter clinical testing The I350T variant in the PGM3 gene has been reported previously (as I322T using alternate nomenclature) in two siblings with immunodeficiency and reduced PGM3 activity (Lundin et al., 2015). In addition, this variant has been identified in the homozygous state in an individual with immunodeficiency and abnormal leukocytes referred for testing at GeneDx. The I350T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The I350T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies reveal that the I350T variant causes a destabilized protein with reduced enzyme activity (Lundin et al., 2015). We interpret I350T as a likely pathogenic variant.
Invitae RCV000554532 SCV000655098 uncertain significance Immunodeficiency 23 2017-07-12 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 350 of the PGM3 protein (p.Ile350Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs745508510, ExAC 0.003%). This variant has been reported to segregate with primary immunodeficiency without hyper-IgE levels in a single family (PMID: 26482871). This variant is also known as p.Ile322Thr in the literature. ClinVar contains an entry for this variant (Variation ID: 421723). Experimental studies have shown that this missense change results in decreased protein stability and reduced enzymatic activity (PMID: 26482871). In summary, this variant disrupts protein function in vitro and segregates with disease in a single family. However, additional functional and/or genetic evidence is needed to conclusively determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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