ClinVar Miner

Submissions for variant NM_144585.4(SLC22A12):c.1400C>T (p.Thr467Met)

gnomAD frequency: 0.00019  dbSNP: rs200104135
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001105887 SCV001262900 uncertain significance Dalmatian hypouricemia 2017-04-27 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001306138 SCV001495497 uncertain significance not provided 2022-10-28 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 467 of the SLC22A12 protein (p.Thr467Met). This variant is present in population databases (rs200104135, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with renal hypouricemia (PMID: 29486147). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 878888). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects SLC22A12 function (PMID: 23386035, 30315176). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital RCV001105887 SCV001984636 likely benign Dalmatian hypouricemia 2019-12-29 criteria provided, single submitter clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV001105887 SCV004807518 uncertain significance Dalmatian hypouricemia 2024-03-29 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004756171 SCV005344638 pathogenic SLC22A12-related disorder 2024-04-09 no assertion criteria provided clinical testing The SLC22A12 c.1400C>T variant is predicted to result in the amino acid substitution p.Thr467Met. This variant has been reported in the compound heterozygous and homozygous states in patients with renal hypouricemia (Stiburkova et al. 2013. PubMed ID: 23386035; Gabrikova et al. 2015. PubMed ID: 26033041). Functional studies of the p.Thr467Met variant showed significantly decreased urate uptake and a mislocalization of the URAT1 protein (Stiburkova et al. 2013. PubMed ID: 23386035). This variant is reported in 0.70% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic.

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