ClinVar Miner

Submissions for variant NM_000030.3(AGXT):c.508G>A (p.Gly170Arg) (rs121908529)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000432954 SCV000511372 likely pathogenic not provided 2016-09-08 criteria provided, single submitter clinical testing
Clinical Biochemistry Laboratory,Health Services Laboratory RCV000032681 SCV000239650 pathogenic Primary hyperoxaluria, type I 2014-11-27 no assertion criteria provided in vitro
Counsyl RCV000032681 SCV000485183 pathogenic Primary hyperoxaluria, type I 2016-03-11 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000432954 SCV000331656 pathogenic not provided 2015-10-09 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000032681 SCV000894272 pathogenic Primary hyperoxaluria, type I 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000432954 SCV000617630 pathogenic not provided 2017-08-22 criteria provided, single submitter clinical testing The G170R variant in the AGXT gene has been reported previously, sometimes using alternate nomenclature G630A, as a common pathogenic variant in association with autosomal recessive primary hyperoxaluria when present in the homozygous state or when in trans with another disease-causing variant (Purdue et al., 1990; Williams et al., 2009; Coulter-Mackie et al., 2014; Hopp et al., 2015). Functional studies show that G170R is associated with mistargeting of the AGT enzyme to the mitochondria rather than to the peroxisomes (Lumb et al., 2000; Montioli et al., 2014). Patients with G170R variant have longer preservation of renal function with conservative treatment compared to other pathogenic variants and respond to pyridoxine treatment, a cofactor that reduces enzyme mistargeting (Monico et al., 2005; Harambat et al., 2010; Hopp et al., 2015). The G170R variant is observed in 41/21670 (0.19%) alleles from individuals of non-Finnish European background in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). The G170R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. We interpret G170R as a pathogenic variant.
GeneReviews RCV000032681 SCV000172454 pathogenic Primary hyperoxaluria, type I 2014-07-17 no assertion criteria provided literature only
Illumina Clinical Services Laboratory,Illumina RCV000032681 SCV000914911 pathogenic Primary hyperoxaluria, type I 2018-09-19 criteria provided, single submitter clinical testing The AGXT c.508G>A (p.Gly170Arg) variant is well described in the literature as one of the most common variants associated with primary hyperoxaluria type 1 (Coulter-Mackie et al. 2014). Across a subset of the literature, the p.Gly170Arg variant has been detected in at least 87 probands, including at least 71 in a homozygous state, at least 93 in a compound heterozygous state, and 30 in a heterozygous state with evidence suggesting these probands were actually compound heterozygous (Purdue et al. 1990; Rumsby et al. 2004; Harambat et al. 2010; Mandrile et al. 2014; Isivel et al 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.001892 in the European (non-Finnish) population of the Exome Aggregation Consortium. Liver biopsies from affected probands found that homozygotes for the p.Gly170Arg had a median AGT activity at 41% of normal, consistent with a less severe phenotype (Harambat et al. 2010). The effects of p.Gly170Arg may be exacerbated due the presence of p.Pro11Leu, also known as the minor allele, in cis which acts as a modifier allele (Williams et al. 2009). Based on the collective evidence, the p.Gly170Arg 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.
Integrated Genetics/Laboratory Corporation of America RCV000589490 SCV000693979 pathogenic Primary hyperoxaluria 2016-12-15 criteria provided, single submitter clinical testing Variant summary: The AGXT c.508G>A (p.Gly170Arg) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 43/42102 control chromosomes at a frequency of 0.0010213, which does not exceed the estimated maximal expected allele frequency of a pathogenic AGXT variant (0.0023717). This variant has been reported as the most common AGXT mutation and found in multiple PH1 patients both as homozygotes and compound heterozygotes. Functional studies showed that G170R causes a folding defect leading to an erroneous targeting to mitochondria, where the enzyme cannot perform glyoxylate detoxification. The AGT mistargeting is due to the combined effects with the P11L polymorphism, which generates a functionally weak N-terminal mitochondrial targeting sequence, and the additional presence of the G170R replacement increases the functional efficiency of this polymorphic mitochondrial targeting sequence. Variant in isolation lead to decreased enzyme activity (~50% WT level, ranging from 40-90% from different reports). However, when variant of interest presents on the minor allele (co-occurrence of two polymorphic variants c.32C>T/P11L and c.1020A>G/I340M), the mutant protein showed non-detectable level of activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000432954 SCV000944322 pathogenic not provided 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 170 of the AGXT protein (p.Gly170Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs121908529, ExAC 0.2%). This variant is the most common mutation reported in individuals affected with primary hyperoxaluria (PMID: 20016466, 24988064), and has been observed to be homozygous or in combination with another AGXT variant in affected individuals (PMID: 1703535, 11708860, 15356974, 15840016, 18985333). This variant is also known as 630G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 40166). Experimental studies have shown that this missense change causes reduced AGT enzyme activity and exhibits significant peroxisome-to-mitochondrion AGT mistargeting in transfected human cells and transgenic mice when it is expressed in cis (on the same chromosome) with the polymorphic change p.Pro11Leu (PMID: 10960483, 23229545, 17110443). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000032681 SCV000966875 pathogenic Primary hyperoxaluria, type I 2018-04-10 criteria provided, single submitter clinical testing The p.Gly170Arg variant in AGXT has been reported in >200 homozygous or compound heterozygous individuals with clinical features of primary hyperoxaluria (PH), representing roughly 25-40% of all alleles in PH patient registries (Harambat 20 10, Mandrile 2014, Hopp 2015). This variant has been identified in 0.1% (111/105 692) of European chromosomes by the Genome Aggregation Database (gnomAD, http:// gnomad.broadinstitute.org; dbSNP rs121908529). In vitro functional studies provi de some evidence that the p.Gly170Arg variant may impact protein function by mis localization and decreased catalytic activity (Fargue 2013); however, these type s of assays may not accurately represent biological function. In summary, this v ariant meets criteria to be classified as pathogenic for primary hyperoxaluriai n an autosomal recessive manner based upon extreme enrichment in PH patients, f unctional evidence, and predicted impact on protein. ACMG/AMP Criteria applied: PM3_VeryStrong; PS4; PS3_Supporting
Laboratory of Medical Genetics,National & Kapodistrian University of Athens RCV000032681 SCV000928384 pathogenic Primary hyperoxaluria, type I 2018-07-27 criteria provided, single submitter clinical testing PS1, PS4, PP3, PP4, PP5
OMIM RCV000032681 SCV000056444 pathogenic Primary hyperoxaluria, type I 2006-11-28 no assertion criteria provided literature only
SIB Swiss Institute of Bioinformatics RCV000032681 SCV000803508 likely pathogenic Primary hyperoxaluria, type I 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Hyperoxaluria, primary, type I, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect on the activity of the minor allele (AGT-Mi). (PMID:19479957) (PMID:17495019) (PMID:10960483). PM2-Supporting =>PM2 downgraded in strength to Supporting (PMID:25644115) (PMID:25644115).

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