Submissions for variant NM_000030.3(AGXT):c.33del (p.Lys12fs)

dbSNP: rs180177201

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169102	SCV000220294	likely pathogenic	Primary hyperoxaluria, type I	2014-05-01	criteria provided, single submitter	literature only
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000169102	SCV000239728	pathogenic	Primary hyperoxaluria, type I	2023-10-27	criteria provided, single submitter	curation	ACMG:PVS1 PM2 PM3 PP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV000794507	SCV000933919	pathogenic	not provided	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys12Argfs*34) in the AGXT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AGXT are known to be pathogenic (PMID: 19479957). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with hyperoxaluria (PMID: 15963748, 17495019, 26383609). ClinVar contains an entry for this variant (Variation ID: 188775). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192774	SCV001361102	pathogenic	Primary hyperoxaluria	2019-02-08	criteria provided, single submitter	clinical testing	Variant summary: AGXT c.33delC (p.Lys12ArgfsX34) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Lys12fsX156, p.Ser275fsX38). The variant was absent in 242874 control chromosomes (gnomAD). c.33delC has been reported in the literature in homozygous individuals affected with Primary Hyperoxaluria Type 1 (Amoroso 2001, Williams 2007, Hoyer-Kuhn_2014). These data indicate that the variant is likely to be associated with disease. One of these publications also measured liver AGT activity in a homozygous patient, and demonstrated a pronounced variant effect, resulting in <10% of normal activity (Williams 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 pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000169102	SCV004047533	pathogenic	Primary hyperoxaluria, type I		criteria provided, single submitter	clinical testing	The frame shift c.33del (p.Lys12ArgfsTer34) variant has been reported previously in homozygous state in patients affected with Hyperoxaluria (Coulter-Mackie MB et al). This p.Lys12ArgfsTer34 variant has allele frequency of 0.0017% in the gnomAD and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Lysine 12, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 34 of the new reading frame, denoted p.Lys12ArgfsTer34. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000169102	SCV004194749	pathogenic	Primary hyperoxaluria, type I	2024-02-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169102	SCV002076447	pathogenic	Primary hyperoxaluria, type I	2020-08-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003895168	SCV004710494	pathogenic	AGXT-related disorder	2023-10-18	no assertion criteria provided	clinical testing	The AGXT c.33delC variant is predicted to result in a frameshift and premature protein termination (p.Lys12Argfs*34). This variant has been reported in multiple individuals with hyperoxaluria (for example see: Coulter-Mackie et al. 2005. PubMed ID: 15963748; Williams et al. 2007. PubMed ID: 17495019). This variant is reported in 0.017% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-241808307-AC-A). Frameshift variants in AGXT are expected to be pathogenic. This variant is interpreted as pathogenic.