Variant summary: The GRHPR c.494G>A (p.Gly165Asp) variant located in the putative cofactor binding site (Cregeen_2003) involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome for this variant. Functional studies support these predictions, which the variant significantly decreases glyoxylate reductase activity (Cregeen_2003 and Webster_200). This variant was found in 17/121252 control chromosomes, predominantly observed in the South Asian cohort at a frequency of 0.000969 (16/16508), which does not exceed the estimated maximal expected allele frequency of a pathogenic GRHPR variant (0.0014434). Multiple publications have cited the variant in affected individuals. In addition, a clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_012203.2(GRHPR):c.494G>A (p.Gly165Asp)
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.
(11)
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
11
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.494G>A (p.Gly165Asp)
Variation ID: 204235 Accession: VCV000204235.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9p13.2 9: 37429732 (GRCh38) [ NCBI UCSC ] 9: 37429729 (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 Jul 21, 2015 Oct 8, 2024 Mar 19, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_012203.2:c.494G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_036335.1:p.Gly165Asp missense NC_000009.12:g.37429732G>A NC_000009.11:g.37429729G>A NG_008135.1:g.12023G>A - Protein change
- G165D
- Other names
- -
- Canonical SPDI
- NC_000009.12:37429731:G:A
-
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.
-
0.00080 (A)
-
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
The Genome Aggregation Database (gnomAD), exomes 0.00012
Exome Aggregation Consortium (ExAC) 0.00014
1000 Genomes Project 30x 0.00062
1000 Genomes Project 0.00080
- 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 (8) |
criteria provided, multiple submitters, no conflicts
|
Mar 19, 2024 | RCV000186442.16 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 26, 2017 | RCV000585941.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 31, 2024 | RCV000802868.7 | |
|
GRHPR-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Dec 11, 2023 | RCV003927729.2 |
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
(May 26, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699330.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The GRHPR c.494G>A (p.Gly165Asp) variant located in the putative cofactor binding site (Cregeen_2003) involves the alteration of a conserved nucleotide and 4/4 in … (more)
Variant summary: The GRHPR c.494G>A (p.Gly165Asp) variant located in the putative cofactor binding site (Cregeen_2003) involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome for this variant. Functional studies support these predictions, which the variant significantly decreases glyoxylate reductase activity (Cregeen_2003 and Webster_200). This variant was found in 17/121252 control chromosomes, predominantly observed in the South Asian cohort at a frequency of 0.000969 (16/16508), which does not exceed the estimated maximal expected allele frequency of a pathogenic GRHPR variant (0.0014434). Multiple publications have cited the variant in affected individuals. In addition, a clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type II
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Suma Genomics
Accession: SCV002543796.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
|
|
|
Pathogenic
(Oct 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type II
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002810400.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Nov 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type II
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024912.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000942714.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 165 of the GRHPR protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 165 of the GRHPR protein (p.Gly165Asp). This variant is present in population databases (rs180177314, gnomAD 0.08%). This missense change has been observed in individual(s) with primary hyperoxaluria type 2 (PMID: 24116921, 25629080, 31685312). ClinVar contains an entry for this variant (Variation ID: 204235). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GRHPR function (PMID: 11030416, 14635115). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type II
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004191695.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(May 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type II
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005329576.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The observed missense variant in splice region c.494G>A(p.Gly165Asp) in GRHPR gene has been reported in homozygous and compound heterozygous state in individuals with primary hyperoxaluria … (more)
The observed missense variant in splice region c.494G>A(p.Gly165Asp) in GRHPR gene has been reported in homozygous and compound heterozygous state in individuals with primary hyperoxaluria type 2 (Takayama T, et al., 2014, Williams EL, et al., 2015). Experimental studies have shown that this missense change affects GRHPR function (Cregeen DP, et al., 2003). The c.494G>A variant has 0.01% allele frequency in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic/Pathogenic (multiple submissions).The amino acid Glycine at position 165 is changed to a Aspartic acid changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen, SIFT and Mutation Taster) predict a damaging effect on protein structure and function for this variant.The amino acid change p.Gly165Asp in GRHPR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the kidney (present)
|
|
|
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: SCV000239796.1
First in ClinVar: Jul 21, 2015 Last updated: Jul 21, 2015 |
Result:
in vitro GR activity 1.5% of control
|
|
|
Likely pathogenic
(Dec 04, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Primary hyperoxaluria, type II
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV001132215.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
|
|
|
Pathogenic
(Dec 30, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Primary hyperoxaluria type II
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002075677.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
|
|
Pathogenic
(Dec 11, 2023)
|
no assertion criteria provided
Method: clinical testing
|
GRHPR-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004738173.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The GRHPR c.494G>A variant is predicted to result in the amino acid substitution p.Gly165Asp. This variant has been reported in several unrelated individuals to be … (more)
The GRHPR c.494G>A variant is predicted to result in the amino acid substitution p.Gly165Asp. This variant has been reported in several unrelated individuals to be causative for primary hyperoxaluria type 2 (Webster et al 2000. PubMed ID: 11030416; Cregeen et al. 2003. PubMed ID: 14635115; Takayama et al. 2014. PubMed ID: 24116921; Garrelfs et al 2019. PubMed ID: 31685312). This variant is predicted to reside in the putative cofactor binding site and was also shown in functional studies to have significantly reduced glyoxylate reductase activity (Webster et al 2000. PubMed ID: 11030416). A recent study identified this variant in 5 individuals with pediatric nephrolithiasis and demonstrated significant differences (p < 0.05) in the enzyme activity between c.494G>A peripheral mononuclear cells (PMCs) and control PMCs (Chatterjee A et al 2022. PubMed ID: 36619171). In summary, the c.494G>A variant is categorized as pathogenic. (less)
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Comment:
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 165 of the GRHPR protein (p.Gly165Asp). This variant is present in population databases (rs180177314, gnomAD 0.08%). This missense change has been observed in individual(s) with primary hyperoxaluria type 2 (PMID: 24116921, 25629080, 31685312). ClinVar contains an entry for this variant (Variation ID: 204235). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GRHPR function (PMID: 11030416, 14635115). For these reasons, this variant has been classified as Pathogenic.
Comment:
The observed missense variant in splice region c.494G>A(p.Gly165Asp) in GRHPR gene has been reported in homozygous and compound heterozygous state in individuals with primary hyperoxaluria type 2 (Takayama T, et al., 2014, Williams EL, et al., 2015). Experimental studies have shown that this missense change affects GRHPR function (Cregeen DP, et al., 2003). The c.494G>A variant has 0.01% allele frequency in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic/Pathogenic (multiple submissions).The amino acid Glycine at position 165 is changed to a Aspartic acid changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen, SIFT and Mutation Taster) predict a damaging effect on protein structure and function for this variant.The amino acid change p.Gly165Asp in GRHPR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Comment:
The GRHPR c.494G>A variant is predicted to result in the amino acid substitution p.Gly165Asp. This variant has been reported in several unrelated individuals to be causative for primary hyperoxaluria type 2 (Webster et al 2000. PubMed ID: 11030416; Cregeen et al. 2003. PubMed ID: 14635115; Takayama et al. 2014. PubMed ID: 24116921; Garrelfs et al 2019. PubMed ID: 31685312). This variant is predicted to reside in the putative cofactor binding site and was also shown in functional studies to have significantly reduced glyoxylate reductase activity (Webster et al 2000. PubMed ID: 11030416). A recent study identified this variant in 5 individuals with pediatric nephrolithiasis and demonstrated significant differences (p < 0.05) in the enzyme activity between c.494G>A peripheral mononuclear cells (PMCs) and control PMCs (Chatterjee A et al 2022. PubMed ID: 36619171). In summary, the c.494G>A variant is categorized as pathogenic.
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:
Variant summary: The GRHPR c.494G>A (p.Gly165Asp) variant located in the putative cofactor binding site (Cregeen_2003) involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome for this variant. Functional studies support these predictions, which the variant significantly decreases glyoxylate reductase activity (Cregeen_2003 and Webster_200). This variant was found in 17/121252 control chromosomes, predominantly observed in the South Asian cohort at a frequency of 0.000969 (16/16508), which does not exceed the estimated maximal expected allele frequency of a pathogenic GRHPR variant (0.0014434). Multiple publications have cited the variant in affected individuals. In addition, a clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 165 of the GRHPR protein (p.Gly165Asp). This variant is present in population databases (rs180177314, gnomAD 0.08%). This missense change has been observed in individual(s) with primary hyperoxaluria type 2 (PMID: 24116921, 25629080, 31685312). ClinVar contains an entry for this variant (Variation ID: 204235). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GRHPR function (PMID: 11030416, 14635115). For these reasons, this variant has been classified as Pathogenic.
Comment:
The observed missense variant in splice region c.494G>A(p.Gly165Asp) in GRHPR gene has been reported in homozygous and compound heterozygous state in individuals with primary hyperoxaluria type 2 (Takayama T, et al., 2014, Williams EL, et al., 2015). Experimental studies have shown that this missense change affects GRHPR function (Cregeen DP, et al., 2003). The c.494G>A variant has 0.01% allele frequency in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic/Pathogenic (multiple submissions).The amino acid Glycine at position 165 is changed to a Aspartic acid changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen, SIFT and Mutation Taster) predict a damaging effect on protein structure and function for this variant.The amino acid change p.Gly165Asp in GRHPR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Comment:
The GRHPR c.494G>A variant is predicted to result in the amino acid substitution p.Gly165Asp. This variant has been reported in several unrelated individuals to be causative for primary hyperoxaluria type 2 (Webster et al 2000. PubMed ID: 11030416; Cregeen et al. 2003. PubMed ID: 14635115; Takayama et al. 2014. PubMed ID: 24116921; Garrelfs et al 2019. PubMed ID: 31685312). This variant is predicted to reside in the putative cofactor binding site and was also shown in functional studies to have significantly reduced glyoxylate reductase activity (Webster et al 2000. PubMed ID: 11030416). A recent study identified this variant in 5 individuals with pediatric nephrolithiasis and demonstrated significant differences (p < 0.05) in the enzyme activity between c.494G>A peripheral mononuclear cells (PMCs) and control PMCs (Chatterjee A et al 2022. PubMed ID: 36619171). In summary, the c.494G>A variant is categorized 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 |
| Performance evaluation of Sanger sequencing for the diagnosis of primary hyperoxaluria and comparison with targeted next generation sequencing. | Williams EL | Molecular genetics & genomic medicine | 2015 | PMID: 25629080 |
| 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 |
| Identification of missense, nonsense, and deletion mutations in the GRHPR gene in patients with primary hyperoxaluria type II (PH2). | Webster KE | Human genetics | 2000 | PMID: 11030416 |
| http://www.uclh.nhs.uk/OurServices/ServiceA-Z/PATH/PATHBIOMED/CBIO/Documents/GRHPR%20mutation%20database.pdf | - | - | - | - |
Text-mined citations for rs180177314 ...
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 Nov 10, 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.