Submissions for variant NM_020975.6(RET):c.487C>T (p.Arg163Trp)

dbSNP: rs371153966

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002327618	SCV002633852	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-18	criteria provided, single submitter	clinical testing	The p.R163W variant (also known as c.487C>T), located in coding exon 3 of the RET gene, results from a C to T substitution at nucleotide position 487. The arginine at codon 163 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, the association of this alteration with Hirschsprung is unknown; however, the association of this alteration with MEN2 is unlikely.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002541758	SCV003249359	uncertain significance	Multiple endocrine neoplasia, type 2	2023-05-23	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 992568). This variant has not been reported in the literature in individuals affected with RET-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 163 of the RET protein (p.Arg163Trp).
Baylor Genetics	RCV004570663	SCV005054181	uncertain significance	Hirschsprung disease, susceptibility to, 1	2024-03-05	criteria provided, single submitter	clinical testing
Klinik und Poliklinik für Kinderchirurgie, Technische Universität Dresden, Universitätsklinikum Carl Gustav Carus	RCV001523789	SCV001450921	uncertain significance	Appendicitis	2020-12-17	no assertion criteria provided	case-control	Variation found in 1 patient (13yrs) with acute ulcerophlegmonous appendicitis. This variant was inherited by the patient's father who also suffered from early appendicitis at 16 yrs.