Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| St. |
RCV001775177 | SCV002012404 | likely pathogenic | Leukemia, acute lymphoblastic, susceptibility to, 3 | 2024-09-23 | criteria provided, single submitter | clinical testing | The PAX5 c.419G>A (p.Arg140Gln) missense change replaces arginine with glutamine at codon 140 of the PAX5 gene and is absent in population databases including gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The arginine residue is highly conserved across species and is a somatic mutational hotspot in pediatric cases of B cell acute lymphoblastic leukemia (PMID: 30487223, 30643249, internal data). This variant has been identified in an individual with B cell acute lymphoblastic leukemia in which the tumor exhibited loss of the wild-type PAX5 allele (internal data). This is consistent with literature reports of individuals with B cell acute lymphoblastic leukemia and pathogenic germline variants in PAX5 (PMID: 24013638, 24287434). Additionally, expression analysis showed that this tumor sample clustered with the PAX5-altered subtype defined by Gu et al. 2019 in PMID: 30643249 (internal data). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. In summary, this variant meets criteria to be classified as likely pathogenic. |
| Ambry Genetics | RCV002573259 | SCV003638268 | likely pathogenic | Inborn genetic diseases | 2022-10-28 | criteria provided, single submitter | clinical testing | The c.419G>A (p.R140Q) alteration is located in exon 4 (coding exon 4) of the PAX5 gene. This alteration results from a G to A substitution at nucleotide position 419, causing the arginine (R) at amino acid position 140 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with clinical features of PAX5-related neurodevelopmental disorder (Gofin, 2022). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. |
| Daryl Scott Lab, |
RCV001580198 | SCV001809830 | pathogenic | Neurodevelopmental disorder | 2021-08-23 | no assertion criteria provided | research |