ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1013C>T (p.Thr338Ile)

gnomAD frequency: 0.00003  dbSNP: rs377767433
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570795 SCV000664515 likely benign Hereditary cancer-predisposing syndrome 2019-01-30 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.
Mendelics RCV000709106 SCV000838375 uncertain significance Multiple endocrine neoplasia type 2A 2018-07-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001046577 SCV001210484 uncertain significance Multiple endocrine neoplasia, type 2 2022-11-01 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 338 of the RET protein (p.Thr338Ile). This variant is present in population databases (rs377767433, gnomAD 0.005%). This missense change has been observed in individual(s) with Hirschsprung's disease and micromedullary thyroid carcinoma (PMID: 11955539, 21810974). ClinVar contains an entry for this variant (Variation ID: 38594). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect RET function (PMID: 21810974, 25440022). 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV001262456 SCV001440343 likely benign Multiple endocrine neoplasia type 2B 2019-01-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV004566792 SCV005054176 uncertain significance Hirschsprung disease, susceptibility to, 1 2024-03-13 criteria provided, single submitter clinical testing
GeneDx RCV004700294 SCV005201970 uncertain significance not provided 2024-02-27 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12939698, 19183406, 11955539, 21810974, 21054478, 20516206, 25440022, 28946813, 30624503, 14633923, 31510104, 35264596)

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