Variant rs80356708 details in Genebe, Genetics Data Aggregator

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:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-37424861-TG-T is Pathogenic according to our data. Variant chr9-37424861-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 5636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRHPR	NM_012203.2 linkuse as main transcript	c.103del	p.Asp35ThrfsTer11	frameshift_variant	2/9	ENST00000318158.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRHPR	ENST00000318158.11 linkuse as main transcript	c.103del	p.Asp35ThrfsTer11	frameshift_variant	2/9	1	NM_012203.2	P1	Q9UBQ7-1

Frequencies

GnomAD3 genomes

AF:

0.000190

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000237

AC:

AN:

248776

Hom.:

AF XY:

0.000237

AC XY:

AN XY:

134922

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000511

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000528

AC:

772

AN:

1461034

Hom.:

Cov.:

AF XY:

0.000466

AC XY:

339

AN XY:

726838

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000378

Gnomad4 NFE exome

AF:

0.000677

Gnomad4 OTH exome

AF:

0.000249

GnomAD4 genome

AF:

0.000190

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.000234

EpiCase

AF:

0.000545

EpiControl

AF:

0.000474

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary hyperoxaluria, type II

Pathogenic:11Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 11, 2017	The p.Asp35ThrfsX11 (NM_012203.1 c.103delG) variant in GRHPR has been reported i n at least 15 homozygous and 1 compound heterozygous individuals with primary hy peroxaluria type II, and segregated in two homozygous affected siblings from two families (Cramer 1999, Webster 2000, Johnson 2002, Cregeen 2003, Rumsby 2003). It is the most common pathogenic variant identified in Caucasian patients with t his disease (Takayama 2014). This variant has also been reported as pathogenic i n ClinVar (Variation ID#5636). The p.Asp35ThrfsX11 variant has been identified i n 21/64772 of European chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs80356708), a frequency low enough to be co nsistent with carrier frequency. This variant is predicted to cause a frameshift , which alters the protein?s amino acid sequence beginning at position 35 and le ads to a premature termination codon 11 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of fu nction of function of the GRHPR gene is an established disease mechanism in prim ary hyperoxaluria type II. In summary, the p.Asp35ThrfsX11 variant meets criteri a to be classified as pathogenic for primary hyperoxaluria type II in an autosom al recessive manner based upon its biallelic occurrence in patients with this di sease and predicted impact on protein function. -
Pathogenic, no assertion criteria provided	research	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 2 of 9). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (68 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. (ClinVar) (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. (ClinVar, PMID: 24116921) (P) 1102 - Strong phenotype match. (P) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 15, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 12, 2018	The GRHPR c.103delG (p.Asp35ThrfsTer11) variant results in frameshift and is predicted to result in premature termination of the protein. The p.Asp35ThrfsTer11 variant is a commonly described pathogenic variant which has been reported in at least three studies in which it was identified in at least 16 individuals diagnosed with primary hyperoxaluria, type 2. The variant was identified in a homozygous state in 14 individuals including two sets of siblings, and in a compound heterozygous state in another two individuals (Cramer et al. 1999; Cregeen et al. 2003; Rumsby et al. 2004). The variant has only been reported in individuals in Caucasian origin (Rumsby et al. 2004). The p.Asp35ThrfsTer11 variant was absent from seven controls but is reported at a frequency of 0.002111 in the African American population of the Exome Sequencing Project. The variant is also found in a homozygous state in eight individuals of the Exome Sequencing Project which could be accounted for by variable phenotypic expression from a severe early onset to asymptomatic form. Enzyme activity in patient liver biopsies has been shown to range from 0-26% of control activity (Cregeen et al. 2003; Rumsby et al. 2004). Based on the collective evidence, the c.103delG (p.Asp35ThrfsTer11) variant is classified as pathogenic for primary hyperoxaluria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 13, 2017	Variant summary: The GRHPR c.103delG (p.Asp35ThrfsX11) variant results in a premature termination codon, predicted to cause a truncated or absent GRHPR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 62/274980 control chromosomes (gnomAD) at a frequency of 0.0002255, 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 homozygote and compound heterozygote pts. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2014	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 19, 2019	NM_012203.1(GRHPR):c.103delG(D35Tfs11) is classified as pathogenic in the context of type 2 primary hyperoxaluria. Sources cited for classification include the following: PMID 15327387, 18560364 and 10484776. Classification of NM_012203.1(GRHPR):c.103delG(D35Tfs11) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 16208537, 24116921, 18560364, 10484776, 31980526, 21228398, 14635115, 15327387, 11030416, 25644115, 28893421, 30609409, 31685312, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Asp35Thrfs*11) in the GRHPR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GRHPR are known to be pathogenic (PMID: 25644115). This variant is present in population databases (rs746720647, gnomAD 0.05%). This premature translational stop signal has been observed in individuals with primary hyperoxaluria (PMID: 10484776, 15327387). ClinVar contains an entry for this variant (Variation ID: 5636). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 02, 2016	- -

Nephrocalcinosis;C0392525:Nephrolithiasis

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Sep 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

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Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

rs80356708

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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