ClinVar Miner

Submissions for variant NM_015599.3(PGM3):c.737A>G (p.Asn246Ser)

dbSNP: rs587777562
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000128844 SCV000266399 pathogenic Immunodeficiency 23 2014-07-03 criteria provided, single submitter research segregates with the phenotype in an affected family
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000128844 SCV002575093 likely pathogenic Immunodeficiency 23 2022-01-21 criteria provided, single submitter clinical testing A Homozygous missense variation in exon 7 of the PGM3 gene that results in the amino acid substitution of Serine for Asparagine at codon 274 was detected. The observed variant c.821A>G (p.Asn274Ser) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are possibly damaging by LRT, MutPred, PROVEAN and MutationTaster. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.
Ambry Genetics RCV003278668 SCV003960067 pathogenic Inborn genetic diseases 2023-05-11 criteria provided, single submitter clinical testing The c.821A>G (p.N274S) alteration is located in exon 7 (coding exon 6) of the PGM3 gene. This alteration results from an A to G substitution at nucleotide position 821, causing the asparagine (N) at amino acid position 274 to be replaced by a serine (S). Based on data from gnomAD, the G allele has an overall frequency of <0.001% (1/250886) total alleles studied. The highest observed frequency was 0.005% (1/18382) of East Asian alleles. This alteration, also known as c.737A>G (p.Asn246Ser), was reported in multiple homozygous individuals with clinical features of PGM3-related immunodeficiency (Stray-Pedersen, 2014; Bernth-Jensen, 2016; NCBI ClinVar 2022). ClinVar citation: National Center for Biotechnology Information. ClinVar; [VCV000140732.3], https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000140732.3 (accessed May 11, 2023). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, N274S is deleterious. The variant disrupts the interaction of Asn274 with metal-binding loop and active serine loop (Stray-Pedersen, 2014; Raimi, 2018). In vitro expression studies in E. coli demonstrated that this substitution abolished PGM3 function with residual function of approximately 1% compared to wild type (Stray-Pedersen, 2014). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
OMIM RCV000128844 SCV000172676 pathogenic Immunodeficiency 23 2014-07-03 no assertion criteria provided literature only

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