rs1052176
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000298.6(PKLR):c.1705C>T(p.Arg569Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000961 in 1,457,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R569Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000298.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKLR | NM_000298.6 | c.1705C>T | p.Arg569Trp | missense_variant | 11/11 | ENST00000342741.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKLR | ENST00000342741.6 | c.1705C>T | p.Arg569Trp | missense_variant | 11/11 | 1 | NM_000298.6 | P3 | |
PKLR | ENST00000392414.7 | c.1612C>T | p.Arg538Trp | missense_variant | 11/11 | 1 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250236Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135374
GnomAD4 exome AF: 0.00000961 AC: 14AN: 1457208Hom.: 0 Cov.: 30 AF XY: 0.00000827 AC XY: 6AN XY: 725254
GnomAD4 genome ? Cov.: 30
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 11, 2022 | - - |
PKLR-related condition Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 20, 2023 | The PKLR c.1705C>T variant is predicted to result in the amino acid substitution p.Arg569Trp. To our knowledge, this variant has not been reported in the literature. However other missense changes at the same amino acid position, c.1706G>A (Arg569Gln) and c.1706G>A (Arg569Gln), have previously been reported in patients with pyruvate kinase deficiency (Pissard et al 2006. PubMed ID: 16704447; Fermo et al 2005. PubMed ID: 15953013). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-155260383-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at