rs180177314

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP5_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:10

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 Likely_pathogenic. Variant got 9 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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/exons	MANE	UniProt
GRHPR	NM_012203.2 linkuse as main transcript	c.494G>A	p.Gly165Asp	missense_variant, splice_region_variant	6/9	ENST00000318158.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRHPR	ENST00000318158.11 linkuse as main transcript	c.494G>A	p.Gly165Asp	missense_variant, splice_region_variant	6/9	1	NM_012203.2	P1	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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary hyperoxaluria, type II

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 23, 2023	- -
Pathogenic, no assertion criteria provided	in vitro	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 30, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 19, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 04, 2016	- -

GRHPR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 11, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

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

May 26, 2017

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. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

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. -

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;.

MutationTaster

Benign

1.0

A;A

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