ClinVar Miner

Submissions for variant NM_000030.3(AGXT):c.836T>C (p.Ile279Thr) (rs140992177)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000180093 SCV000232462 benign not specified 2015-04-15 criteria provided, single submitter clinical testing
Invitae RCV000966394 SCV001113712 likely benign not provided 2020-12-08 criteria provided, single submitter clinical testing
Mendelics RCV000186256 SCV001136275 benign Primary hyperoxaluria, type I 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000186256 SCV001297134 likely benign Primary hyperoxaluria, type I 2017-08-25 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Clinical Biochemistry Laboratory,Health Services Laboratory RCV000186256 SCV000239580 uncertain significance Primary hyperoxaluria, type I 2014-11-27 no assertion criteria provided in vitro
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000966394 SCV001549730 likely benign not provided no assertion criteria provided clinical testing The AGXT p.Ile279Thr variant was identified in the literature in 4/55 probands with type 1 primary hyperoxaluria, however in three of these probands already carried two presumed pathogenic variants (Monico_2007_PMID:17460142). The variant was also found in two other cases of type 1 primary hyperoxaluria but was found on the same allele as the c.33_34ins variant (Coulter-Mackie_2005_PMID:15963748). The variant was identified in dbSNP (ID: rs140992177), ClinVar (classified as benign by EGL Genetic Diagnostics and as uncertain significance by Clinical Biochemistry Laboratory, Health Services Laboratory) and LOVD 3.0 (classified as likely pathogenic). The variant was identified in control databases in 510 of 282628 chromosomes at a frequency of 0.001804 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 380 of 129022 chromosomes (freq: 0.002945), South Asian in 71 of 30608 chromosomes (freq: 0.00232), Other in 11 of 7222 chromosomes (freq: 0.001523), European (Finnish) in 16 of 25118 chromosomes (freq: 0.000637), Latino in 16 of 35412 chromosomes (freq: 0.000452), African in 11 of 24942 chromosomes (freq: 0.000441), Ashkenazi Jewish in 3 of 10360 chromosomes (freq: 0.00029), and East Asian in 2 of 19944 chromosomes (freq: 0.0001). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Ile279 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Functional analysis of alanine:glyoxylate aminotransferase activity was not found to be affected with the p.I279T variant. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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