ClinVar Genomic variation as it relates to human health
NM_000298.6(PKLR):c.1436G>A (p.Arg479His)
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.1436G>A (p.Arg479His)
Variation ID: 1510 Accession: VCV000001510.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 155293177 (GRCh38) [ NCBI UCSC ] 1: 155262968 (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 Apr 4, 2013 Feb 4, 2024 Sep 19, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000298.6:c.1436G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000289.1:p.Arg479His missense NM_000298.5:c.1436G>A NM_000298.5:c.[1436G>A] NM_181871.4:c.1343G>A NP_870986.1:p.Arg448His missense NC_000001.11:g.155293177C>T NC_000001.10:g.155262968C>T NG_011677.1:g.13258G>A LRG_1136:g.13258G>A LRG_1136t1:c.1436G>A LRG_1136p1:p.Arg479His P30613:p.Arg479His - Protein change
- R479H, R448H
- Other names
- -
- Canonical SPDI
- NC_000001.11:155293176:C:T
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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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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
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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 |
301 | 328 |
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 (2) |
criteria provided, single submitter
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- | RCV000001574.13 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 19, 2022 | RCV001781165.20 |
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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Pathogenic
(Jan 09, 2020)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604838.2
First in ClinVar: Sep 30, 2017 Last updated: Jan 26, 2021 |
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Pathogenic
(Sep 19, 2022)
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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: SCV002018836.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(-)
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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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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073050.1
First in ClinVar: Feb 05, 2022 Last updated: Feb 05, 2022 |
Comment:
The missense variant p.R479H in PKLR (NM_000298.6) has been reported in homozygous state in affected patients including those of the Amish ancestry (Kedar P et … (more)
The missense variant p.R479H in PKLR (NM_000298.6) has been reported in homozygous state in affected patients including those of the Amish ancestry (Kedar P et al; Bowman HS et al). The variant has been submitted to ClinVar as Pathogenic. In silico tools predict the variant to be damaging and the residue is conserved across species.For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Decreased serum testosterone concentration (present) , Abnormal pituitary gland morphology (present) , Primary amenorrhea (present) , Abnormality of the ovary (present)
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Pathogenic
(Oct 14, 2021)
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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: SCV002245466.1
First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022 |
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Pathogenic
(Jul 01, 2022)
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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: SCV002765856.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Published functional studies demonstrate a damaging effect (damage of natural splice donor site resulting in exon skipping and alteration of kinetic property) (Valentini et al., … (more)
Published functional studies demonstrate a damaging effect (damage of natural splice donor site resulting in exon skipping and alteration of kinetic property) (Valentini et al., 2002; Wijk et al., 2004); In silico analysis supports that this missense variant has a splicing effect; 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: 8161798, 16704447, 18759866, 15059150, 31028937, 32036089, 34987744, 11960989) (less)
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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, AMISH TYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021730.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In the form of pyruvate kinase deficiency (266200) observed among the Old Order Amish of Pennsylvania by Bowman and Procopio (1963) and Bowman et al. … (more)
In the form of pyruvate kinase deficiency (266200) observed among the Old Order Amish of Pennsylvania by Bowman and Procopio (1963) and Bowman et al. (1965), Kanno et al. (1994) identified a 1436G-A transition in the PKLR gene, resulting in an arg479-to-his (R479H) substitution. Valentini et al. (2002) demonstrated that although the R479H substitution occurs in the allosteric site of the PK enzyme, it does not interfere with kinetic parameters. They observed that the 1436G-A change may affect a splicing site at the 3-prime end of exon 10, resulting in abnormal splicing. Kedar et al. (2009) identified the R479H mutation in 7 (19.4%) of 36 alleles in 18 Indian patients with PK deficiency. (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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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 |
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 abnormality of erythrocyte pyruvate kinase deficiency in the Amish. | Kanno H | Blood | 1994 | PMID: 8161798 |
PYRUVATE KINASE DEFICIENT HEMOLYTIC ANEMIA IN AN AMISH ISOLATE. | BOWMAN HS | American journal of human genetics | 1965 | PMID: 14255553 |
Hereditary non-spherocytic hemolytic anemia of the pyruvate-kinase deficient type. | BOWMAN HS | Annals of internal medicine | 1963 | PMID: 14014643 |
Text-mined citations for rs118204085 ...
HelpRecord last updated Jul 23, 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.