ClinVar Miner

Submissions for variant NM_000030.3(AGXT):c.731T>C (p.Ile244Thr) (rs121908525)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clinical Biochemistry Laboratory,Health Services Laboratory RCV000006000 SCV000239674 pathogenic Primary hyperoxaluria, type I 2014-11-27 no assertion criteria provided in vitro
Counsyl RCV000006000 SCV000485184 pathogenic Primary hyperoxaluria, type I 2016-03-11 criteria provided, single submitter clinical testing
GeneReviews RCV000006000 SCV000172457 pathogenic Primary hyperoxaluria, type I 2014-07-17 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000586265 SCV000693980 pathogenic Primary hyperoxaluria 2017-05-07 criteria provided, single submitter clinical testing Variant summary: The AGXT c.731T>C (p.Ile244Thr) variant involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 4/121328 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic AGXT variant (0.0023717). Multiple publications have cited the variant in affected indiviudals and has been implicated to be a Spain founder mutation. As would be expected of a founder effect, other polymorphisms and regional microsatellites within the AGXT gene are shared in this founder haplotype and have been reported to further modify the effect of this variant. Functional studies have shown that the variant alone acts comparable to wild type enzymatic activity (Santana_2003 and Lumb_2000), however, in cis with another variant, in particular, P11L, the enzymatic activity is loss. Rumsby_2004 found that homozygous individuals had limited enzymatic activity, although it is unclear whether the commonly found P11L was found in cis with these individuals. Furthermore, Rumsby_2004, citing the study by Santana_2003, states that c.731T>C mutation has approximately 50% of normal activity when expressed with Pro11 but less than 5% of activity when expressed with Leu11. At-least one additional report by Monico_2007 cites a patient diagnosed at age 1 to be compound heterozygous for this variant and another pathogenic variant described as IVS8-3C>G (c.847-3C>G in ClinVar). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic, but should be noted that the variant of interest seems to be influenced by particular variants observed in cis.
OMIM RCV000006000 SCV000026182 pathogenic Primary hyperoxaluria, type I 2013-01-25 no assertion criteria provided literature only
Yale Center for Mendelian Genomics,Yale University RCV000662316 SCV000784648 likely pathogenic Nephrocalcinosis; Nephrolithiasis 2017-09-08 no assertion criteria provided literature only

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