Submissions for variant NM_000030.3(AGXT):c.697C>T (p.Arg233Cys)

gnomAD frequency: 0.00005  dbSNP: rs121908526

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000006001	SCV001162945	pathogenic	Primary hyperoxaluria, type I		criteria provided, single submitter	clinical testing
Invitae	RCV001070457	SCV001235689	pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 233 of the AGXT protein (p.Arg233Cys). This variant is present in population databases (rs121908526, gnomAD 0.04%). This missense change has been observed in individual(s) with primary hyperoxaluria type I (PMID: 9192270, 10862087, 17495019, 18282470, 25629080). ClinVar contains an entry for this variant (Variation ID: 5647). 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 AGXT protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AGXT function (PMID: 18448374, 18782763). This variant disrupts the p.Arg233 amino acid residue in AGXT. Other variant(s) that disrupt this residue have been observed in individuals with AGXT-related conditions (PMID: 9192270, 15849466, 17460142, 25629080), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001070457	SCV001873464	pathogenic	not provided	2022-09-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect by impairing protein level and in vitro acitivity for both the R233C major allele and the R233C minor allele with the P11L and I340M substitutions, although the in vitro activity and protein levels were lower for the R233C minor allele (Hopper et al., 2008); This variant is associated with the following publications: (PMID: 18782763, 9192270, 17495019, 10862087, 18448374, 20301460, 18282470, 24988064, 25629080, 33274618, 28906061, 31589614)
Myriad Genetics, Inc.	RCV000006001	SCV002060387	likely pathogenic	Primary hyperoxaluria, type I	2021-11-03	criteria provided, single submitter	clinical testing	NM_000030.2(AGXT):c.697C>T(R233C) is a missense variant classified as likely pathogenic in the context of primary hyperoxaluria type 1. R233C has been observed in cases with relevant disease (PMID: 10862087, 18282470, 25629080). Functional assessments of this variant are available in the literature (PMID: 18782763, 17495019, 18448374). Internal structural analysis of the variant is supportive of pathogenicity. R233C has been observed in population frequency databases (gnomAD: AFR 0.04%). In summary, NM_000030.2(AGXT):c.697C>T(R233C) is a missense variant that has internal structural support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Fulgent Genetics, Fulgent Genetics	RCV000006001	SCV002776118	pathogenic	Primary hyperoxaluria, type I	2022-03-17	criteria provided, single submitter	clinical testing
OMIM	RCV000006001	SCV000026183	pathogenic	Primary hyperoxaluria, type I	1997-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000006001	SCV000172456	not provided	Primary hyperoxaluria, type I		no assertion provided	literature only
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000006001	SCV000239670	pathogenic	Primary hyperoxaluria, type I	2014-11-27	no assertion criteria provided	in vitro
Natera, Inc.	RCV000006001	SCV001456050	pathogenic	Primary hyperoxaluria, type I	2020-09-16	no assertion criteria provided	clinical testing