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

gnomAD frequency: 0.00001  dbSNP: rs745508510

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480499	SCV000571015	likely pathogenic	not provided	2023-01-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on enzyme activity (Ludin et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 1245758, 35040011, 26482871)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000554532	SCV000655098	uncertain significance	Immunodeficiency 23	2022-07-29	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 350 of the PGM3 protein (p.Ile350Thr). This variant is present in population databases (rs745508510, gnomAD 0.003%). This missense change has been observed in individual(s) with primary immunodeficiency without hyper-IgE levels (PMID: 26482871). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Ile322Thr. ClinVar contains an entry for this variant (Variation ID: 421723). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C45"). Experimental studies have shown that this missense change affects PGM3 function (PMID: 26482871). 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000554532	SCV000898869	uncertain significance	Immunodeficiency 23	2021-12-22	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.
Revvity Omics, Revvity	RCV000554532	SCV002018775	pathogenic	Immunodeficiency 23	2022-04-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767295	SCV005380989	likely pathogenic	Severe combined immunodeficiency disease	2024-08-15	criteria provided, single submitter	clinical testing	Variant summary: PGM3 c.1049T>C (p.Ile350Thr) results in a non-conservative amino acid change located in the Phosphoacetylglucosamine mutase AMG1, domain III (IPR049022) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251152 control chromosomes. c.1049T>C has been reported in the literature in homozygous and compound heterozygous individuals affected with Severe Combined Immunodeficiency (Lundin_2015, Winslow_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 480% of normal enzyme activity in an in vitro assay (Lundin_2015). The following publications have been ascertained in the context of this evaluation (PMID: 26482871, 35040011). ClinVar contains an entry for this variant (Variation ID: 421723). Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM	RCV000554532	SCV001426379	pathogenic	Immunodeficiency 23	2020-07-30	no assertion criteria provided	literature only