ClinVar Miner

Submissions for variant NM_000353.3(TAT):c.1250G>A (p.Arg417Gln)

gnomAD frequency: 0.00001  dbSNP: rs757879229
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000664686 SCV000788687 uncertain significance Tyrosinemia type II 2018-04-04 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000664686 SCV002186054 pathogenic Tyrosinemia type II 2022-11-28 criteria provided, single submitter clinical testing This variant is present in population databases (rs757879229, gnomAD 0.003%). This missense change has been observed in individual(s) with tyrosinemia (PMID: 21145993, 28255985; Invitae). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 417 of the TAT protein (p.Arg417Gln). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TAT protein function. ClinVar contains an entry for this variant (Variation ID: 550062).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004702273 SCV005203421 uncertain significance not specified 2024-07-18 criteria provided, single submitter clinical testing Variant summary: TAT c.1250G>A (p.Arg417Gln) results in a conservative amino acid change located in the Aminotransferase, class I/classII domain (IPR004839) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251370 control chromosomes. c.1250G>A has been reported in the literature in at least one homozygous individual affected with Tyrosinemia Type 2 (e.g. Culic_2011). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 21145993). ClinVar contains an entry for this variant (Variation ID: 550062). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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