Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mayo Clinic Laboratories, |
RCV001508883 | SCV001715314 | likely pathogenic | not provided | 2020-08-04 | criteria provided, single submitter | clinical testing | PM1, PM2_supporting, PM3, PP3 |
| Revvity Omics, |
RCV001508883 | SCV002024657 | pathogenic | not provided | 2023-07-18 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001508883 | SCV004252954 | pathogenic | not provided | 2023-11-21 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 331 of the PKLR protein (p.Asp331Glu). This variant is present in population databases (rs138476691, gnomAD 0.03%). This missense change has been observed in individual(s) with pyruvate kinase deficiency (PMID: 7706479, 9657767, 10354117, 17360088, 29519373). ClinVar contains an entry for this variant (Variation ID: 1163643). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PKLR protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
| ARUP Laboratories, |
RCV001508883 | SCV004563944 | likely pathogenic | not provided | 2023-09-14 | criteria provided, single submitter | clinical testing | The PKLR c.993C>A; p.Asp331Glu variant (rs138476691) is reported in the literature in two individuals affected with PK deficiency (Baronciani 1995, Svidnicki 2018). This variant is also reported in ClinVar (Variation ID: 1163643). This variant is found in the general population with an overall allele frequency of 0.008% (24/282626 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.942). Additionally, other variants at this codon (c.992A>G, p.Asp331Gly; c.991G>A, p.Asp331Asn) have been reported in individuals with PK deficiency and are considered disease causing (Baronciani 1998, Gupta 2007, Jamwal 2020). Based on available information, this variant is considered to be likely pathogenic. REFERENCES Baronciani L et al. Molecular study of pyruvate kinase deficient patients with hereditary nonspherocytic hemolytic anemia. J Clin Invest. 1995 Apr. PMID: 7706479 Baronciani L et al. Hematologically important mutations: red cell pyruvate kinase (2nd update). Blood Cells Mol Dis. 1998 Sep. PMID: 10087985 Gupta N et al. Prenatal diagnosis for a novel homozygous mutation in PKLR gene in an Indian family. Prenat Diagn. 2007 Feb. PMID: 17191259 Jamwal M et al. Next-Generation Sequencing-Based Diagnosis of Unexplained Inherited Hemolytic Anemias Reveals Wide Genetic and Phenotypic Heterogeneity. J Mol Diagn. 2020 Apr. PMID: 32036089 Svidnicki M et al. Novel mutations associated with pyruvate kinase deficiency in Brazil. Rev Bras Hematol Hemoter. 2018 Jan - Mar. PMID: 29519373 |