Submissions for variant NM_012203.2(GRHPR):c.337G>A (p.Glu113Lys)

gnomAD frequency: 0.00001  dbSNP: rs180177307

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169087	SCV000220264	likely pathogenic	Primary hyperoxaluria, type II	2014-04-22	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169087	SCV001983634	likely pathogenic	Primary hyperoxaluria, type II	2021-09-13	criteria provided, single submitter	clinical testing	Variant summary: GRHPR c.337G>A (p.Glu113Lys) results in a conservative amino acid change located in the D-isomer specific 2-hydroxyacid dehydrogenase, catalytic domain (IPR006139) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251480 control chromosomes. c.337G>A has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with Primary Hyperoxaluria Type 2 (example, Takayama_2007, Hopp_2015). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in abolishment of normal GRHPR enzyme activity in an in-vitro COS-1 experimental system (Takayama_2007). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517625	SCV003440926	likely pathogenic	not provided	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 113 of the GRHPR protein (p.Glu113Lys). This variant is present in population databases (rs180177307, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of primary hyperoxaluria type 2 (PMID: 17510093, 35149915). ClinVar contains an entry for this variant (Variation ID: 188765). 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 80%. Experimental studies have shown that this missense change affects GRHPR function (PMID: 17510093). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV000169087	SCV004191712	likely pathogenic	Primary hyperoxaluria, type II	2024-02-20	criteria provided, single submitter	clinical testing
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000169087	SCV000239794	pathogenic	Primary hyperoxaluria, type II	2014-11-27	no assertion criteria provided	in vitro
Chinese Inherited Urolithiasis Consortium, The Affiliated Yantai Yuhuangding Hospital of Qingdao University	RCV000169087	SCV005368606	likely pathogenic	Primary hyperoxaluria, type II	2024-08-26	no assertion criteria provided	clinical testing	Variant_type:missense/MutationTaster:Disease_causing_automatic/CADD:Damaging/phyloP:Conserved/phastCons:Conserved/gnomAD_exome_EastAsian:0/ExAC_EastAsian:-/dbSNP:rs180177307