ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs180177307
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Total submissions: 5
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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.
Invitae 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 2023-08-11 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

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