ClinVar Miner

Submissions for variant NM_003227.4(TFR2):c.1409G>T (p.Ser470Ile)

gnomAD frequency: 0.00001  dbSNP: rs772104483
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000700023 SCV000828759 pathogenic Hereditary hemochromatosis 2024-08-08 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 470 of the TFR2 protein (p.Ser470Ile). This variant is present in population databases (rs772104483, gnomAD 0.006%). This missense change has been observed in individual(s) with hereditary hemochromatosis (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 577309). 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 TFR2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004689861 SCV005185756 uncertain significance not specified 2024-05-15 criteria provided, single submitter clinical testing Variant summary: TFR2 c.1409G>T (p.Ser470Ile) results in a non-conservative amino acid change located in the Peptidase M28 (IPR007484) 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 251076 control chromosomes. c.1409G>T has been reported in the literature in the homozygous state in at least 1 individual affected with Hemochromatosis Type 3 (example, Khayat_2019). 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 have been ascertained in the context of this evaluation (PMID: 29985876). ClinVar contains an entry for this variant (Variation ID: 577309). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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