ClinVar Miner

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

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Total submissions: 8
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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 not specified 2019-06-14 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
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.

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