ClinVar Genomic variation as it relates to human health
NM_000298.6(PKLR):c.1456C>T (p.Arg486Trp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000298.6(PKLR):c.1456C>T (p.Arg486Trp)
Variation ID: 1513 Accession: VCV000001513.61
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 155291918 (GRCh38) [ NCBI UCSC ] 1: 155261709 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 14, 2016 Apr 20, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000298.6:c.1456C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000289.1:p.Arg486Trp missense NM_181871.4:c.1363C>T NP_870986.1:p.Arg455Trp missense NC_000001.11:g.155291918G>A NC_000001.10:g.155261709G>A NG_011677.1:g.14517C>T LRG_1136:g.14517C>T LRG_1136t1:c.1456C>T LRG_1136p1:p.Arg486Trp P30613:p.Arg486Trp - Protein change
- R486W, R455W
- Other names
- -
- Canonical SPDI
- NC_000001.11:155291917:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00160 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00270
1000 Genomes Project 0.00160
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00208
Exome Aggregation Consortium (ExAC) 0.00285
The Genome Aggregation Database (gnomAD), exomes 0.00305
1000 Genomes Project 30x 0.00172
Trans-Omics for Precision Medicine (TOPMed) 0.00229
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PKLR | - | - |
GRCh38 GRCh38 GRCh37 |
297 | 324 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2024 | RCV000001577.29 | |
Pathogenic (1) |
criteria provided, single submitter
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May 28, 2022 | RCV000762857.11 | |
Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Feb 6, 2024 | RCV000724015.50 | |
Pathogenic (2) |
criteria provided, single submitter
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May 4, 2022 | RCV000991156.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 13, 2020 | RCV002251854.9 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Apr 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331623.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 8
Sex: mixed
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Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Pyruvate kinase hyperactivity
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002518869.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Likely pathogenic
(May 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Pyruvate kinase deficiency of red cells
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002521511.1
First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001513). A different missense … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001513). A different missense change at the same codon (p.Arg486Leu) has been reported to be associated with PKLR related disorder (PMID: 16704447). It is observed in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset at total allele frequency of 0.305%. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.83). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Reticulocytosis (present) , Chronic hemolytic anemia (present) , Hepatosplenomegaly (present) , Neonatal hyperbilirubinemia (present) , Hyperbilirubinemia (present)
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Pathogenic
(May 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713042.2
First in ClinVar: Jun 15, 2021 Last updated: Jun 03, 2023 |
Comment:
PS4, PM1, PM3, PP4, PP5
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Pathogenic
(Nov 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024662.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Feb 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004243293.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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Likely Pathogenic
(Dec 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Pyruvate kinase deficiency of red cells
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000713497.4
First in ClinVar: Apr 09, 2018 Last updated: Apr 20, 2024 |
Comment:
The p.Arg486Trp variant in PKLR has been reported in >30 compound heterozygous individuals with pyruvate kinase deficiency and segregated in 1 affected relative (PKD; Baronciani … (more)
The p.Arg486Trp variant in PKLR has been reported in >30 compound heterozygous individuals with pyruvate kinase deficiency and segregated in 1 affected relative (PKD; Baronciani 1993 PMID:8483951, Zarza 1998 PMID:9827908, Manco 2000 PMID:11054094, Zanella 2001 PMID:11328279, Kedar 2009 PMID:18759866, Kager 2016 PMID:26728349, Jaouani 2017 PMID:28133914, Canu 2020 PMID:32974842, Milanesio 2021, Jamwal 2020 PMIDL32036089). It has also been identified in 0.812% (204/25114) of Finnish (unknown frequency of PKD) and 0.29% (375/128890) of European chromosomes (1:20,000 frequency of PKD) by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID 1513). Enzymatic studies suggest that the p.Arg486Trp variant may be a mild mutation with reduced activity (Zarza 1998 PMID:9827908, Zanella 2001 PMID:11328279, Valentini 2002 PMID:11960989, and Kedar 2009 PMID:18759866). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg486Trp variant meets criteria to be classified as likely pathogenic for autosomal recessive pyruvate kinase deficiency. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate. (less)
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Likely pathogenic
(Jan 27, 2016)
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criteria provided, single submitter
Method: clinical testing
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Pyruvate kinase deficiency of red cells
Affected status: no
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Study: CSER-NextGen
Accession: SCV000223943.2 First in ClinVar: Oct 05, 2015 Last updated: Apr 20, 2017 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Nov 13, 2020)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523854.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
ACMG classification criteria: PS3, PS4, PM3, PP1, PP3, PP4, BS2
Clinical Features:
Autosomal recessive inheritance (present)
Geographic origin: Brazil
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Pathogenic
(Sep 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Pyruvate kinase deficiency of red cells
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, Heidelberg University
Accession: SCV002757812.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
Sex: male
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Pathogenic
(May 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Pyruvate kinase hyperactivity
Pyruvate kinase deficiency of red cells
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893217.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Likely pathogenic
(May 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001792018.2
First in ClinVar: Aug 18, 2021 Last updated: May 13, 2023 |
Comment:
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: 30681718, … (more)
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: 30681718, 29555771, 27871768, 32279356, 31980526, 29549173, 32165483, 11960989, 20981092, 8483951, 11054094, 24533562, 29349879, 29519373, 29519369, 11328279, 9827908, 18759866, 27346685, 29396846, 30358897, 28133914, 9482576, 32036089, 32543069, 32043619, 30609409, 31974203, 32974842, 26728349, 18708292, 33054133, 33054047, 23770304, 33054048, 34426522, 34662886, 33631127) (less)
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Pathogenic
(Jan 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pyruvate kinase deficiency of red cells
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004171978.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
Comment:
The missense c.1456C>T (p.Arg486Trp) variant in PKLR gene has been reported previously (as the most common variant) in compound heterozygous state in multiple individuals affected … (more)
The missense c.1456C>T (p.Arg486Trp) variant in PKLR gene has been reported previously (as the most common variant) in compound heterozygous state in multiple individuals affected with pyruvate kinase deficiency (Montllor et al. 2017; Jaouani et al. 2017; Canu et al. 2020). Experimental evidence shows that this variant is more thermoresistant than the wild type, did not induce significant conformational changes in the overall protein conformation, and leads to a drastic reduction in catalytic efficiency, which is consistent with a moderate phenotype (Valentini et al. 2002). The p.Arg486Trp variant is reported with an allele frequency of 0.3% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Arg486Trp in PKLR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 486 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pyruvate kinase deficiency of red cells
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004223638.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: PKLR c.1456C>T (p.Arg486Trp) results in a non-conservative amino acid change located in the Pyruvate Kinase C terminal domain (IPR015795) of the encoded protein … (more)
Variant summary: PKLR c.1456C>T (p.Arg486Trp) results in a non-conservative amino acid change located in the Pyruvate Kinase C terminal domain (IPR015795) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.003 in 251132 control chromosomes in the gnomAD database, including 2 homozygotes. c.1456C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with moderate to severe Pyruvate Kinase Deficiency Of Red Cells (examples: Zanella_1997, Pastore_1998, Pissard_2006 ). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence that this variant moderately affects PKLR function (example: Valentini_2002). Fifteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001035168.5
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 486 of the PKLR protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 486 of the PKLR protein (p.Arg486Trp). This variant is present in population databases (rs116100695, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with pyruvate kinase deficiency (PMID: 9057665, 9657767, 9827908, 11054094, 17574881, 27871768, 32974842). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is commonly associated with mild to asymptomatic disease when observed in the homozygous state. However, this variant in conjunction with another pathogenic variant is a common cause of mild chronic hemolytic anemia, particularly in populations of southern Europe. Instances of moderate to severe disease in association with this variant have also been reported (PMID: 17360088, 9482576, 11328279, 10354117). ClinVar contains an entry for this variant (Variation ID: 1513). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PKLR protein function with a negative predictive value of 80%. Experimental studies have shown that this variant moderately affects PKLR function (PMID: 11960989). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885966.7
First in ClinVar: Dec 15, 2018 Last updated: Feb 20, 2024 |
Comment:
The PKLR c.1456C>T; p.Arg486Trp variant (rs116100695), is reported in the literature as both a homozygous and compound heterozygous variant in several individuals affected with pyruvate … (more)
The PKLR c.1456C>T; p.Arg486Trp variant (rs116100695), is reported in the literature as both a homozygous and compound heterozygous variant in several individuals affected with pyruvate kinase deficiency (Baronciani 1993, Kedar 2009, Manco 2000, Zanella 2001, Zarza 1998). This variant is reported in ClinVar (Variation ID: 1513). This variant is found in the general population with an overall allele frequency of 0.3% (833/282498 alleles, including two homozygotes) in the Genome Aggregation Database. Additionally, an alternative change at the same amino acid location (c.1457G>T, p.Arg486Leu) that is known to affect the PK activity has also been reported in an individual with hemolytic anemia (Pissard 2006). The arginine at codon 486 is moderately conserved and computational analyses predict that this variant is deleterious (REVEL 0.91). Based on available information, this variant is considered to be pathogenic. References: Baronciani L et al. Analysis of pyruvate kinase-deficiency mutations that produce nonspherocytic hemolytic anemia. Proc Natl Acad Sci U S A. 1993 90:4324-4327. Kedar P et al. Spectrum of novel mutations in the human PKLR gene in pyruvate kinase-deficient Indian patients with heterogeneous clinical phenotypes. Clin Genet. 2009 75:157-162. Manco L et al. A new PKLR gene mutation in the R-type promoter region affects the gene transcription causing pyruvate kinase deficiency. Br J Haematol. 2000 110:993-997. Pissard S et al. Pyruvate kinase deficiency in France: a 3-year study reveals 27 new mutations. Br J Haematol. 2006 133:683-689. Zanella A et al. Molecular characterization of the PK-LR gene in sixteen pyruvate kinase-deficient patients. Br J Haematol. 2001 113:43-48. Zarza R et al. Molecular characterization of the PK-LR gene in pyruvate kinase deficient Spanish patients. Red Cell Pathology Group of the Spanish Society of Haematology (AEHH). Br J Haematol. 1998 103:377-382. (less)
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Pathogenic
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Pyruvate kinase deficiency of red cells
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004808207.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Apr 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001746867.14
First in ClinVar: Jul 10, 2021 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 2
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Pathogenic
(Feb 01, 2009)
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no assertion criteria provided
Method: literature only
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PYRUVATE KINASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021733.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 14, 2016 |
Comment on evidence:
Zarza et al. (1998) found that the most frequent mutation of the PKLR gene causing pyruvate kinase deficiency (266200) and hereditary nonspherocytic hemolytic anemia in … (more)
Zarza et al. (1998) found that the most frequent mutation of the PKLR gene causing pyruvate kinase deficiency (266200) and hereditary nonspherocytic hemolytic anemia in Spain is a 1456C-T transition, resulting in an arg486-to-trp (R486W) substitution. The mutation was identified in approximately one-third of mutant alleles (7 of 22). Zanella et al. (2001) found that the R486W mutation appeared to be the most frequent mutation causing hemolytic anemia associated with PK deficiency in Italy. Kedar et al. (2009) identified the R486W mutation in 6 (16.7%) of 36 alleles in 18 Indian patients with PK deficiency. (less)
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Pathogenic
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Adenosine triphosphate, elevated, of erythrocytes
Affected status: unknown
Allele origin:
germline
|
Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142310.1
First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550687.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
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 … (more)
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. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Six novel variants in the PKLR gene associated with pyruvate kinase deficiency in Argentinian patients. | Milanesio B | Clinical biochemistry | 2021 | PMID: 33631127 |
Identification and in silico characterization of a novel PKLR genotype in a Turkish newborn. | Canu G | Molecular biology reports | 2020 | PMID: 32974842 |
Next-Generation Sequencing-Based Diagnosis of Unexplained Inherited Hemolytic Anemias Reveals Wide Genetic and Phenotypic Heterogeneity. | Jamwal M | The Journal of molecular diagnostics : JMD | 2020 | PMID: 32036089 |
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project. | Ceyhan-Birsoy O | American journal of human genetics | 2019 | PMID: 30609409 |
Precision medicine screening using whole-genome sequencing and advanced imaging to identify disease risk in adults. | Perkins BA | Proceedings of the National Academy of Sciences of the United States of America | 2018 | PMID: 29555771 |
Multi-gene panel testing improves diagnosis and management of patients with hereditary anemias. | Russo R | American journal of hematology | 2018 | PMID: 29396846 |
Molecular basis of pyruvate kinase deficiency among Tunisians: description of new mutations affecting coding and noncoding regions in the PKLR gene. | Jaouani M | International journal of laboratory hematology | 2017 | PMID: 28133914 |
Red cell pyruvate kinase deficiency in Spain: A study of 15 cases. | Montllor L | Medicina clinica | 2017 | PMID: 27871768 |
Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits. | Chami N | American journal of human genetics | 2016 | PMID: 27346685 |
Two Novel Missense Mutations and a 5bp Deletion in the Erythroid-Specific Promoter of the PKLR Gene in Two Unrelated Patients With Pyruvate Kinase Deficient Transfusion-Dependent Chronic Nonspherocytic Hemolytic Anemia. | Kager L | Pediatric blood & cancer | 2016 | PMID: 26728349 |
Modulation of Malaria Phenotypes by Pyruvate Kinase (PKLR) Variants in a Thai Population. | van Bruggen R | PloS one | 2015 | PMID: 26658699 |
Spectrum of novel mutations in the human PKLR gene in pyruvate kinase-deficient Indian patients with heterogeneous clinical phenotypes. | Kedar P | Clinical genetics | 2009 | PMID: 18759866 |
Pyruvate kinase deficient hemolytic anemia in the Northern Irish population. | Percy MJ | Blood cells, molecules & diseases | 2007 | PMID: 17574881 |
Pyruvate kinase deficiency: the genotype-phenotype association. | Zanella A | Blood reviews | 2007 | PMID: 17360088 |
Pyruvate kinase deficiency in France: a 3-year study reveals 27 new mutations. | Pissard S | British journal of haematology | 2006 | PMID: 16704447 |
Red cell pyruvate kinase deficiency: molecular and clinical aspects. | Zanella A | British journal of haematology | 2005 | PMID: 15982340 |
Structure and function of human erythrocyte pyruvate kinase. Molecular basis of nonspherocytic hemolytic anemia. | Valentini G | The Journal of biological chemistry | 2002 | PMID: 11960989 |
Molecular characterization of the PK-LR gene in sixteen pyruvate kinase-deficient patients. | Zanella A | British journal of haematology | 2001 | PMID: 11328279 |
A new PKLR gene mutation in the R-type promoter region affects the gene transcription causing pyruvate kinase deficiency. | Manco L | British journal of haematology | 2000 | PMID: 11054094 |
Estimating the prevalence of pyruvate kinase deficiency from the gene frequency in the general white population. | Beutler E | Blood | 2000 | PMID: 10828047 |
PK-LR gene mutations in pyruvate kinase deficient Portuguese patients. | Manco L | British journal of haematology | 1999 | PMID: 10354117 |
Molecular characterization of the PK-LR gene in pyruvate kinase deficient Spanish patients. Red Cell Pathology Group of the Spanish Society of Haematology (AEHH). | Zarza R | British journal of haematology | 1998 | PMID: 9827908 |
Six previously undescribed pyruvate kinase mutations causing enzyme deficiency. | Demina A | Blood | 1998 | PMID: 9657767 |
Novel mutations and structural implications in R-type pyruvate kinase-deficient patients from Southern Italy. | Pastore L | Human mutation | 1998 | PMID: 9482576 |
Molecular characterization of PK-LR gene in pyruvate kinase-deficient Italian patients. | Zanella A | Blood | 1997 | PMID: 9160692 |
Molecular analysis of 29 pyruvate kinase-deficient patients from central Europe with hereditary hemolytic anemia. | Lenzner C | Blood | 1997 | PMID: 9057665 |
Analysis of pyruvate kinase-deficiency mutations that produce nonspherocytic hemolytic anemia. | Baronciani L | Proceedings of the National Academy of Sciences of the United States of America | 1993 | PMID: 8483951 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PKLR | - | - | - | - |
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Text-mined citations for rs116100695 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.