ClinVar Miner

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

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Total submissions: 7
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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 2017-09-06 criteria provided, single submitter clinical testing The p.Arg486Trp variant in PKLR has been reported in >25 compound heterozygous i ndividual with pyruvate kinase deficiency (Zarza 1998, Manco 2000, Zanella 2001, Kedar 2009, Kager 2016, Jaouani 2017, Baronciani 1993). This variant has also b een reported in ClinVar (Variation ID#1513) as likely pathogenic by two laborato ries. Enzymatic studies suggest that the p.Arg486Trp variant may be a mild mutat ion with reduced activity (Zarza 1998, Zanella 2001, Valentini 2002, and Kedar 2 009). This variant has been identified in 0.294% (372/126444) of European chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg; dbSNP rs116100695), though this frequency is low enough to be consistent wit h a recessive carrier frequency. In summary, although additional studies are req uired to fully establish its clinical significance, the p.Arg486Trp variant is l ikely pathogenic for pyruvate kinase deficiency in an autosomal recessive manner based upon biallelic occurrence in affected individuals and enzymatic studies. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000724015 SCV000885966 pathogenic not provided 2017-08-10 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 2019-02-22 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

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