ClinVar Miner

Submissions for variant NM_015599.3(PGM3):c.1612C>A (p.Pro538Thr)

gnomAD frequency: 0.00019  dbSNP: rs143654268
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000239095 SCV000297068 uncertain significance not specified 2015-11-20 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001067238 SCV001232285 uncertain significance Immunodeficiency 23 2022-10-17 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 566 of the PGM3 protein (p.Pro566Thr). This variant is present in population databases (rs143654268, gnomAD 0.08%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with PGM3-related conditions. ClinVar contains an entry for this variant (Variation ID: 252565). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Molecular Genetics, Royal Melbourne Hospital RCV001067238 SCV002498614 uncertain significance Immunodeficiency 23 2022-04-05 criteria provided, single submitter clinical testing This sequence change in PGM3 is predicted to replace proline with threonine at codon 538, p.(Pro538Thr). The proline residue is evolutionarily conserved (100 vertebrates, UCSC), and is not located in a known functional domain. There is a small physicochemical difference between proline and threonine. The highest population minor allele frequency in gnomAD v2.1 is 0.09% (110/128,980 alleles, 1 homozygote) in the European (non-Finnish) population. This variant has been reported as a variant of uncertain significance (ClinVar ID: 252565), and to our knowledge has not been reported in the literature in any individuals with immunodeficiency. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3.

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