ClinVar Miner

Submissions for variant NM_000298.6(PKLR):c.1456C>T (p.Arg486Trp) (rs116100695)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000001577 SCV000223943 likely pathogenic Pyruvate kinase deficiency of red cells 2016-01-27 criteria provided, single submitter clinical testing The c.1456C>T (p.Arg486Trp) (NM_ 000298.5) missense variant has been reported in several unrelated individuals diagnosed with PK deficiency. These families have a well-documented clinical history of anemia (Zarza et al. 1998). Case-control studies have reported this variant as a common disease causing variant accounting for 9%-32% of diagnosed cases (Zarza et al., 1998; Zanella et al., 2001; Kedar et al., 2009). This variant has often been reported in trans with several pathogenic variants, and functional studies have shown that patients harboring this variant, in a compound heterozygous state, have reduced PK activity relative to normal controls (Zarza et al., 1998; Zanella et al., 2001; Valentini et al. 2002; Kedar et al., 2009). This c.1456C>T variant is reported at low frequency in the population databases (ESP = 0.291%; 1000 Genomes = 1%; ExAC = 0.298%), and multiple in silico algorithms predict this variant to have a deleterious effect (GERP = 4.85; CADD = 18.75; PolyPhen = 1; SIFT = 0). Therefore, this collective evidence supports the classification of the c.1456C>T (p.Arg486Trp) variant as a recessive Likely Pathogenic variant for PK deficiency.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724015 SCV000331623 likely pathogenic not provided 2017-04-14 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000001577 SCV000713497 likely pathogenic Pyruvate kinase deficiency of red cells 2020-03-30 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000050 SCV000885966 pathogenic none provided 2020-08-04 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762857 SCV000893217 pathogenic Adenosine triphosphate, elevated, of erythrocytes; Pyruvate kinase deficiency of red cells 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000724015 SCV001035168 likely benign not provided 2019-12-31 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000724015 SCV001713042 pathogenic not provided 2020-08-21 criteria provided, single submitter clinical testing PS4, PM1, PM3, PP4, PP5, BS2
CeGaT Praxis fuer Humangenetik Tuebingen RCV000724015 SCV001746867 pathogenic not provided 2021-04-01 criteria provided, single submitter clinical testing
GeneDx RCV000724015 SCV001792018 likely pathogenic not provided 2021-02-03 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18708292, 26728349, 32165483, 33054048, 23770304, 29549173, 33054047, 33054133, 32974842, 31974203, 30609409, 32043619, 32543069, 32036089, 9482576, 32279356, 28133914, 30358897, 29396846, 27346685, 18759866, 9827908, 11328279, 29519369, 29519373, 29349879, 24533562, 11054094, 8483951, 20981092, 11960989, 30681718, 29555771, 27871768, 31980526)
OMIM RCV000001577 SCV000021733 pathogenic Pyruvate kinase deficiency of red cells 2009-02-01 no assertion criteria provided literature only
Reproductive Health Research and Development,BGI Genomics RCV000991156 SCV001142310 pathogenic Adenosine triphosphate, elevated, of erythrocytes 2020-01-06 no assertion criteria provided curation NM_000298.5:c.1456C>T in the PKLR gene has an allele frequency of 0.008 in European (Finnish) subpopulation in the gnomAD database. This variant has been reported in multiple individuals with Pyruvate kinase deficiency, in a compound heterozygous state: 1190A>T/1456C>T, 1042-1044del/1456C>T, 992A>G/1456C>T, 1436G>A/1456C>T (PMID: 18759866); 1456C>T/1675C>T, 1456C>T/1010G>A, 1456C>T/1223C>T, 1456C>T/1070T>C, 1456C>T/721G>T(PMID: 9827908). Functional studies suggest that the p.Arg486Trp variant may be a mild mutation with reduced enzyme activity (PMID: 11960989).Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3, PP4.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000724015 SCV001550687 pathogenic not provided no assertion criteria provided clinical testing The PKLR p.R486W variant was identified in over 30 individuals with pyruvate kinase deficiency and haemolytic anemia as a compound heterozygous variant; phenotypes ranged from mild to severe (Russo_2018_PMID:29396846; Jaouani_2017_PMID:28133914; Montllor_2016_PMID:27871768; Kedar_2009_PMID:18759866; Zanella_2001_PMID:11328279; Manco_2000_PMID:11054094; Zarza_1998_PMID:9827908; Baronciani_1993_PMID:8483951; Marcello_2008_PMID:18708292). The variant was identified in dbSNP (ID: rs116100695) and ClinVar (classified as pathogenic by Fulgent Genetics, ARUP Laboratories and Reproductive Health Research and Development, BGI Genomics, as likely pathogenic by Laboratory of Molecular Medicine, EGL Genetics and Knight Diagnostic Laboratories, Oregon Health and Services University, and as likely benign by Invitae). The variant was identified in control databases in 833 of 282498 chromosomes (2 homozygous) at a frequency of 0.002949 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 204 of 25114 chromosomes (freq: 0.008123), South Asian in 113 of 30616 chromosomes (freq: 0.003691), European (non-Finnish) in 375 of 128890 chromosomes (freq: 0.002909), Other in 20 of 7218 chromosomes (freq: 0.002771), Ashkenazi Jewish in 28 of 10360 chromosomes (freq: 0.002703), Latino in 80 of 35424 chromosomes (freq: 0.002258) and African in 13 of 24926 chromosomes (freq: 0.000522), but was not observed in the East Asian population. Although the p.R486 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. Functional data suggests that this variant results in decreased catalytic efficiency (Valentini_2002_PMID:11960989). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.