ClinVar Genomic variation as it relates to human health
NM_000194.3(HPRT1):c.143G>A (p.Arg48His)
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_000194.3(HPRT1):c.143G>A (p.Arg48His)
Variation ID: 29985 Accession: VCV000029985.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq26.2 X: 134475189 (GRCh38) [ NCBI UCSC ] X: 133609219 (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 Sep 30, 2017 May 12, 2024 Dec 5, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000194.3:c.143G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000185.1:p.Arg48His missense NC_000023.11:g.134475189G>A NC_000023.10:g.133609219G>A NG_012329.2:g.20045G>A P00492:p.Arg48His - Protein change
- R48H
- Other names
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- Canonical SPDI
- NC_000023.11:134475188: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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HPRT1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
226 | 420 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (1) |
no assertion criteria provided
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Jan 1, 2011 | RCV000022877.6 | |
Pathogenic (2) |
criteria provided, single submitter
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Dec 20, 2022 | RCV000690811.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 1, 2017 | RCV001092162.17 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 1, 2011 | RCV001255647.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 5, 2023 | RCV003492300.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 18, 2023 | RCV003398561.4 |
Submissions - Germline
Classification
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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
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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
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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
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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
(Aug 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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HPRT1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004119141.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The HPRT1 c.143G>A variant is predicted to result in the amino acid substitution p.Arg48His. This variant has been reported in multiple individuals with hyperuricemia with … (more)
The HPRT1 c.143G>A variant is predicted to result in the amino acid substitution p.Arg48His. This variant has been reported in multiple individuals with hyperuricemia with or without neurological symptoms (see for example, Table 1, Sege-Peterson et al. 1992. PubMed ID: 1301916; Table 1, Sampat et al. 2010. PubMed ID: 20981450; Sapag et al. 2012. PubMed ID: 22999896). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. An in vitro experimental study suggests this variant impacts protein function (Figure 1, Sampat et al. 2010. PubMed ID: 20981450). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Nov 01, 2017)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248543.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Dec 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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HPRT1-Related Disorders
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004241836.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: HPRT1 c.143G>A (p.Arg48His) results in a non-conservative amino acid change located in the Phosphoribosyltransferase domain (IPR000836) of the encoded protein sequence. Five of … (more)
Variant summary: HPRT1 c.143G>A (p.Arg48His) results in a non-conservative amino acid change located in the Phosphoribosyltransferase domain (IPR000836) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183163 control chromosomes (gnomAD). c.143G>A has been reported in the literature in multiple individuals affected with HPRT1-Related Disorders (e.g., Sampat_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a reduced maximum rate of reaction in vitro and also leads to poor thermal stability (e.g., Sampat_2011). The following publication was ascertained in the context of this evaluation (PMID: 20981450). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Lesch-Nyhan syndrome
Partial hypoxanthine-guanine phosphoribosyltransferase deficiency
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000818539.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HPRT1 function (PMID: 20981450, 25481104). Algorithms … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HPRT1 function (PMID: 20981450, 25481104). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 29985). This missense change has been observed in individuals with HPRT1-related disease (PMID: 1301916, 10737990, 17454734, 20981450, 22157001, 22999896). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 48 of the HPRT1 protein (p.Arg48His). (less)
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Pathogenic
(Jan 01, 2011)
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no assertion criteria provided
Method: literature only
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LESCH-NYHAN SYNDROME, NEUROLOGIC VARIANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000044168.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2020 |
Comment on evidence:
In 9 patients from 7 unrelated families with the neurologic variant of Lesch-Nyhan syndrome (see 300322), Sampat et al. (2011) identified a 143G-A transition in … (more)
In 9 patients from 7 unrelated families with the neurologic variant of Lesch-Nyhan syndrome (see 300322), Sampat et al. (2011) identified a 143G-A transition in the HPRT gene, resulting in an arg48-to-his (R48H) substitution in an alpha-2 helix at the interface between dimerization of the protein. An additional patient with hyperuricemia and impulsive/oppositional behavior, whom the authors classified as having HPRT-related hyperuricemia (HRH; 300323), also carried the mutation. The mutation likely arose independently multiple times, because it occurred at a CpG motif. There was almost no detectable HPRT enzyme activity in patient erythrocytes, but there was some residual activity in patient fibroblasts. Kinetic studies in E. coli showed that the mutant enzyme had normal affinity for hypoxanthine and guanine, but V(max) was decreased by 33% and 37% for those substrates, respectively, compared to wildtype. However, additional studies showed that the mutant protein had poor thermal stability, with only 16% residual activity at 37 degrees C and undetectable activity at 55 degrees C, which may have explained the variable phenotypic consequences in mutation carriers. (less)
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Pathogenic
(Jan 01, 2011)
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no assertion criteria provided
Method: literature only
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HYPERURICEMIA, HPRT-RELATED
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001432208.1
First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020 |
Comment on evidence:
In 9 patients from 7 unrelated families with the neurologic variant of Lesch-Nyhan syndrome (see 300322), Sampat et al. (2011) identified a 143G-A transition in … (more)
In 9 patients from 7 unrelated families with the neurologic variant of Lesch-Nyhan syndrome (see 300322), Sampat et al. (2011) identified a 143G-A transition in the HPRT gene, resulting in an arg48-to-his (R48H) substitution in an alpha-2 helix at the interface between dimerization of the protein. An additional patient with hyperuricemia and impulsive/oppositional behavior, whom the authors classified as having HPRT-related hyperuricemia (HRH; 300323), also carried the mutation. The mutation likely arose independently multiple times, because it occurred at a CpG motif. There was almost no detectable HPRT enzyme activity in patient erythrocytes, but there was some residual activity in patient fibroblasts. Kinetic studies in E. coli showed that the mutant enzyme had normal affinity for hypoxanthine and guanine, but V(max) was decreased by 33% and 37% for those substrates, respectively, compared to wildtype. However, additional studies showed that the mutant protein had poor thermal stability, with only 16% residual activity at 37 degrees C and undetectable activity at 55 degrees C, which may have explained the variable phenotypic consequences in mutation carriers. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Partial hypoxanthine-guanine phosphoribosyltransferase deficiency
Lesch-Nyhan syndrome
Affected status: yes
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749812.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Pathogenic and reported on 09-23-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpreted as Pathogenic and reported on 09-23-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Abnormal muscle physiology (present) , Abnormal aggressive, impulsive or violent behavior (present) , Autistic behavior (present) , Abnormal delivery (present) , Pregnancy history (present) , … (more)
Abnormal muscle physiology (present) , Abnormal aggressive, impulsive or violent behavior (present) , Autistic behavior (present) , Abnormal delivery (present) , Pregnancy history (present) , Maternal teratogenic exposure (present) , Premature birth (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Testing laboratory: Invitae
Date variant was reported to submitter: 2019-09-23
Testing laboratory interpretation: Pathogenic
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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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Clinical severity in Lesch-Nyhan disease: the role of residual enzyme and compensatory pathways. | Fu R | Molecular genetics and metabolism | 2015 | PMID: 25481104 |
Hypoxanthine-guanine phosphoribosyltransferase deficiency in a patient with a Madrid II mutation. | Sapag A | Joint bone spine | 2013 | PMID: 22999896 |
Genotype-phenotype correlations in Lesch-Nyhan disease: moving beyond the gene. | Fu R | The Journal of biological chemistry | 2012 | PMID: 22157001 |
Mechanisms for phenotypic variation in Lesch-Nyhan disease and its variants. | Sampat R | Human genetics | 2011 | PMID: 20981450 |
Hypoxanthine-guanine phosphoribosyltransferase deficiency: biochemical and molecular findings in six Argentine patients. | Laróvere LE | Nucleosides, nucleotides & nucleic acids | 2007 | PMID: 17454734 |
Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in thirteen Spanish families. | Torres RJ | Human mutation | 2000 | PMID: 10737990 |
Characterization of mutations in phenotypic variants of hypoxanthine phosphoribosyltransferase deficiency. | Sege-Peterson K | Human molecular genetics | 1992 | PMID: 1301916 |
Text-mined citations for rs387906725 ...
HelpRecord last updated May 12, 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.