This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 302 of the GRHPR protein (p.Arg302Cys). This variant is present in population databases (rs180177322, gnomAD 0.02%). This missense change has been observed in individual(s) with primary hyperoxaluria type 2 (PMID: 14635115, 24116921, 31685312). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 162022). 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 expected to disrupt GRHPR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GRHPR function (PMID: 14635115). This variant disrupts the p.Arg302 amino acid residue in GRHPR. Other variant(s) that disrupt this residue have been observed in individuals with GRHPR-related conditions (PMID: 25644115), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_012203.2(GRHPR):c.904C>T (p.Arg302Cys)
Germline
Classification
Help
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.
(8)
Help
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.
Pathogenic/Likely pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_012203.2(GRHPR):c.904C>T (p.Arg302Cys)
Variation ID: 162022 Accession: VCV000162022.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9p13.2 9: 37436699 (GRCh38) [ NCBI UCSC ] 9: 37436696 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 May 8, 2015 Jun 17, 2024 Feb 16, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_012203.2:c.904C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_036335.1:p.Arg302Cys missense NC_000009.12:g.37436699C>T NC_000009.11:g.37436696C>T NG_008135.1:g.18990C>T - Protein change
- R302C
- Other names
- -
- Canonical SPDI
- NC_000009.12:37436698:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| GRHPR | - | - |
GRCh38 GRCh37 |
548 | 624 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Feb 16, 2024 | RCV000149443.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 11, 2024 | RCV000794534.7 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Feb 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type II
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004191703.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Likely pathogenic
(Jul 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type II
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002806312.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000933948.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 302 of the GRHPR protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 302 of the GRHPR protein (p.Arg302Cys). This variant is present in population databases (rs180177322, gnomAD 0.02%). This missense change has been observed in individual(s) with primary hyperoxaluria type 2 (PMID: 14635115, 24116921, 31685312). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 162022). 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 expected to disrupt GRHPR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GRHPR function (PMID: 14635115). This variant disrupts the p.Arg302 amino acid residue in GRHPR. Other variant(s) that disrupt this residue have been observed in individuals with GRHPR-related conditions (PMID: 25644115), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: curation
|
Primary hyperoxaluria, type II
Affected status: no
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051807.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
|
Likely pathogenic
(Jul 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type II
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581178.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PM5, PS3_SUP, PS4_SUP, PM2_SUP, PP3
|
Number of individuals with the variant: 2
Sex: female
|
|
|
Pathogenic
(Oct 01, 2014)
|
no assertion criteria provided
Method: literature only
|
HYPEROXALURIA, PRIMARY, TYPE II
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000196081.2
First in ClinVar: Dec 21, 2014 Last updated: May 08, 2015 |
Comment on evidence:
For discussion of the arg302-to-cys (R302C) mutation in the GRHPR gene that was found in compound heterozygous state in a patient with type II primary … (more)
For discussion of the arg302-to-cys (R302C) mutation in the GRHPR gene that was found in compound heterozygous state in a patient with type II primary hyperoxaluria (HP2; 260000) by Takayama et al. (2014), see 604296.0004. (less)
|
|
|
Likely pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Primary hyperoxaluria type II
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001462569.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(Nov 27, 2014)
|
no assertion criteria provided
Method: in vitro
|
Primary hyperoxaluria, type II
Affected status: yes
Allele origin:
germline
|
Clinical Biochemistry Laboratory, Health Services Laboratory
Accession: SCV000239798.1
First in ClinVar: Jul 21, 2015 Last updated: Jul 21, 2015 |
Result:
in vitro GR activity 5.6% of control
|
Comment:
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. |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 302 of the GRHPR protein (p.Arg302Cys). This variant is present in population databases (rs180177322, gnomAD 0.02%). This missense change has been observed in individual(s) with primary hyperoxaluria type 2 (PMID: 14635115, 24116921, 31685312). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 162022). 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 expected to disrupt GRHPR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GRHPR function (PMID: 14635115). This variant disrupts the p.Arg302 amino acid residue in GRHPR. Other variant(s) that disrupt this residue have been observed in individuals with GRHPR-related conditions (PMID: 25644115), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Patients with primary hyperoxaluria type 2 have significant morbidity and require careful follow-up. | Garrelfs SF | Kidney international | 2019 | PMID: 31685312 |
| Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria. | Hopp K | Journal of the American Society of Nephrology : JASN | 2015 | PMID: 25644115 |
| Ethnic differences in GRHPR mutations in patients with primary hyperoxaluria type 2. | Takayama T | Clinical genetics | 2014 | PMID: 24116921 |
| Molecular analysis of the glyoxylate reductase (GRHPR) gene and description of mutations underlying primary hyperoxaluria type 2. | Cregeen DP | Human mutation | 2003 | PMID: 14635115 |
| http://www.uclh.nhs.uk/OurServices/ServiceA-Z/PATH/PATHBIOMED/CBIO/Documents/GRHPR%20mutation%20database.pdf | - | - | - | - |
Text-mined citations for rs180177322 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.