Submissions for variant NM_012203.2(GRHPR):c.955G>T (p.Gly319Trp)

gnomAD frequency: 0.00018  dbSNP: rs142835989

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000490104	SCV000577773	likely pathogenic	not provided	2015-05-21	criteria provided, single submitter	clinical testing	The G319W variant in the GRHPR gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The G319W variant was not observed with a significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G319W variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (N312D, M322R) have been reported in the Human Gene Mutation Database in association with hyperoxaluria (Stenson et al., 2014), supporting the functional importance of this region of the protein. The G319W variant is a strong candidate for a disease-causing variants, however the possibility it may be a rare benign variant cannot be excluded.
Illumina Laboratory Services, Illumina	RCV001167414	SCV001329910	uncertain significance	Primary hyperoxaluria, type II	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000490104	SCV001418301	uncertain significance	not provided	2022-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 319 of the GRHPR protein (p.Gly319Trp). This variant is present in population databases (rs142835989, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with GRHPR-related conditions. ClinVar contains an entry for this variant (Variation ID: 427140). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.