ClinVar Miner

Submissions for variant NM_020975.6(RET):c.3113C>T (p.Thr1038Ile)

gnomAD frequency: 0.00002  dbSNP: rs200021472
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000228519 SCV000290557 uncertain significance Multiple endocrine neoplasia, type 2 2025-01-30 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1038 of the RET protein (p.Thr1038Ile). This variant is present in population databases (rs200021472, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 241356). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Ambry Genetics RCV000567853 SCV000674830 likely benign Hereditary cancer-predisposing syndrome 2023-05-18 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx RCV001589196 SCV001825537 uncertain significance not provided 2023-10-26 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24336963, 25733075, 30653986, 14633923)
Genetic Services Laboratory, University of Chicago RCV001820760 SCV002070049 uncertain significance not specified 2020-01-03 criteria provided, single submitter clinical testing DNA sequence analysis of the RET gene demonstrated a sequence change, c.3113C>T, in exon 19 that results in an amino acid change, p.Thr1038Ile. This sequence change does not appear to have been previously described in patients with RET-related disorders and has been described in the gnomAD database with a frequency of 0.004% in European populations (dbSNP rs200021472). The p.Thr1038Ile change affects a highly conserved amino acid residue located in a domain of the RET protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr1038Ile substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr1038Ile change remains unknown at this time.
Fulgent Genetics, Fulgent Genetics RCV002500812 SCV002788267 uncertain significance Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A 2022-05-26 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000228519 SCV004838717 uncertain significance Multiple endocrine neoplasia, type 2 2024-09-23 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 1038 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/282850 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics RCV004567757 SCV005054175 uncertain significance Hirschsprung disease, susceptibility to, 1 2024-03-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001589196 SCV005623100 uncertain significance not provided 2023-11-24 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.