rs180177314

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_012203.2(GRHPR):c.494G>A(p.Gly165Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000692 in 1,604,618 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000079 ( 1 hom., cov: 35)

Exomes 𝑓: 0.000068 ( 1 hom. )

Consequence

GRHPR
NM_012203.2 missense, splice_region

Scores

Splicing: ADA: 0.9995

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 8.27

Variant links:

Genes affected

GRHPR (HGNC:4570): (glyoxylate and hydroxypyruvate reductase) This gene encodes an enzyme with hydroxypyruvate reductase, glyoxylate reductase, and D-glycerate dehydrogenase enzymatic activities. The enzyme has widespread tissue expression and has a role in metabolism. Type II hyperoxaluria is caused by mutations in this gene. [provided by RefSeq, Jul 2008]

GRHPR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

PP5

Variant 9-37429732-G-A is Pathogenic according to our data. Variant chr9-37429732-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 204235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37429732-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHPR	NM_012203.2 link	c.494G>A	p.Gly165Asp	missense_variant, splice_region_variant	Exon 6 of 9	ENST00000318158.11	NP_036335.1	Q9UBQ7-1A0A384N605

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHPR	ENST00000318158.11 link	c.494G>A	p.Gly165Asp	missense_variant, splice_region_variant	Exon 6 of 9	1	NM_012203.2	ENSP00000313432.6		Q9UBQ7-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00227

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000115

AC:

AN:

251456

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000915

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000682

AC:

AN:

1452240

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

723226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00101

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000453

Gnomad4 OTH exome

AF:

0.0000999

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152378

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74530

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000140

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary hyperoxaluria, type II

Pathogenic:8

Nov 27, 2014

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: in vitro

- -

Mar 19, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 23, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 04, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.494G>A(p.Gly165Asp) variant in GRHPR gene has been reported previously in homozygous state in individual(s) affected with Pediatric nephrolithiasis (NL) (Chatterjee et al., 2022). Experimental studies have shown that this missense change affects GRHPR function (Cregeen et al., 2003). This variant is reported with the allele frequency of 0.01% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The amino acid Gly at position 165 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly165Asp in GRHPR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen - Possibly Damaging, SIFT - Damaging, and MutationTaster - Disease causing automatic) predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. The same variant in GRHPR [c.494G>A (p.Gly165Asp)] gene has been detected in heterozygous state in spouse. -

Dec 30, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Jan 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 03, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (PMID: 11030416, 14635115); 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: 28660284, 11030416, 31685312, 14635115, 24116921, 14987413, 19296982, 16756993, 25629080, 35046417, 37881736, 36619171, 33752806, 38737343, 37803380) -

GRHPR-related disorder

Pathogenic:1

Dec 11, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Primary hyperoxaluria

Pathogenic:1

May 26, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

H;.

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-6.9

D;.

REVEL

Pathogenic

0.99

Sift

Uncertain

0.0010

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.98

MutPred

0.96

Loss of MoRF binding (P = 0.0432);Loss of MoRF binding (P = 0.0432);

MVP

0.99

MPC

1.4

ClinPred

0.98

GERP RS

5.4

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.3

Varity_R

1.0

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over