Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002512654 | SCV003523512 | pathogenic | not provided | 2022-08-24 | criteria provided, single submitter | clinical testing | This variant disrupts a region of the PKLR protein in which other variant(s) (p.Glu407Lys) have been determined to be pathogenic (PMID: 16704447, 18759866). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 8 (also referred to as exon 9 using alternate exon numbering), but is expected to preserve the integrity of the reading-frame (PMID: 9166866). ClinVar contains an entry for this variant (Variation ID: 1517). This variant has been observed in individual(s) with pyruvate kinase deficiency (PMID: 9166866, 18420493). This variant is present in population databases (rs774652817, gnomAD 0.006%). This sequence change affects codon 423 of the PKLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PKLR protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. For these reasons, this variant has been classified as Pathogenic. |
| Revvity Omics, |
RCV002512654 | SCV003817537 | likely pathogenic | not provided | 2021-11-30 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV005041964 | SCV005675052 | likely pathogenic | Pyruvate kinase hyperactivity; Pyruvate kinase deficiency of red cells | 2024-01-31 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV002512654 | SCV005875585 | pathogenic | not provided | 2024-06-07 | criteria provided, single submitter | clinical testing | The PKLR c.1269G>A; p.Ala423= variant (rs774652817, ClinVar ID: 1517), also known as PK ‘Kamata’, is reported in the literature, both as compound heterozygous and homozygous, in individuals with pyruvate kinase deficiency (Ayi 2008, Kanno 1997). In vitro functional analyses demonstrate skipping of exon 9 due to aberrant splicing, causing a deletion of 51 amino acids in the RBC subunit of PKLR (Kanno 1997). This variant is found in the general population with an overall allele frequency of 0.001% (3/282842 alleles) in the Genome Aggregation Database. Additionally, an alternative change at this position (c.1269G>C, p.Ala423=) has been reported in an individual with pyruvate kinase deficiency (Zanella 1997). This is a synonymous variant in a highly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Based on available information, this variant is considered to be pathogenic. References: Ayi K et al. Pyruvate kinase deficiency and malaria. N Engl J Med. 2008 Apr 24. PMID: 18420493. Kanno H et al. Frame shift mutation, exon skipping, and a two-codon deletion caused by splice site mutations account for pyruvate kinase deficiency. Blood. 1997 Jun 1. PMID: 9166866. Zanella A et al. Molecular characterization of PK-LR gene in pyruvate kinase-deficient Italian patients. Blood. 1997 May 15. PMID: 9160692. |
| OMIM | RCV000001581 | SCV000021737 | pathogenic | Pyruvate kinase deficiency of red cells | 2008-04-24 | no assertion criteria provided | literature only |