Submissions for variant NM_020975.6(RET):c.3148C>T (p.Arg1050Ter)

dbSNP: rs767479170

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001819981	SCV002067439	likely pathogenic	not provided	2020-02-17	criteria provided, single submitter	clinical testing	DNA sequence analysis of the RET gene demonstrated a sequence change, c.3148C>T, which results in the creation of a premature stop codon at amino acid position 1050, p.Arg1050*. This likely pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated RET protein with potentially abnormal function. This sequence change has not been described in population databases (gnomAD, ExAC). The p.Arg1050* change has been reported in an individual with Hirschsprung disease (PMID: 22174939) and in a terminated fetus with bilateral multicystic dysplastic kidneys and anhydramnios (PMID: 29194579). This sequence change was identified to have been inherited from the fetus's healthy father who was reported to have no kidney anomalies, no symptoms of Hirschsprung disease or multiple endocrine neoplasia type 2, and no relevant family history. Other truncating variants in the region have been described in individuals with Hirschsprung disease.
Ambry Genetics	RCV004035575	SCV005028380	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-02-28	criteria provided, single submitter	clinical testing	The p.R1050* variant (also known as c.3148C>T), located in coding exon 19 of the RET gene, results from a C to T substitution at nucleotide position 3148. This changes the amino acid from an arginine to a stop codon within coding exon 19. This alteration occurs at the 3' terminus of theRET gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 65 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected and the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in multiple patients with Hirschsprung disease (So MT et al. PLoS One, 2011 Dec;6:e28986; Gui H et al. Hum Genet, 2013 May;132:591-600; Jiang Q et al. Genet Med, 2018 Jul;20:770-777; Tang CS et al. Gastroenterology, 2018 Dec;155:1908-1922.e5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is likely pathogenic for Hirschsprung disease; however, the association of this alteration with MEN2 is unknown.
GeneDx	RCV001819981	SCV005628307	pathogenic	not provided	2024-07-15	criteria provided, single submitter	clinical testing	Identified in several individuals with Hirschsprung disease in published literature (PMID: 22174939, 29261189, 30217742); Identified in fetal cases with congenital anomalies of the kidney and urinary tract (PMID: 29194579, 36307859); Nonsense variant predicted to result in protein truncation, as the last 65 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23400839, 22174939, 14633923, 34981673, 29194579, 36307859, 29261189, 30217742)
Klinik und Poliklinik für Kinderchirurgie, Technische Universität Dresden, Universitätsklinikum Carl Gustav Carus	RCV001289999	SCV001469012	uncertain significance	Appendicitis	2020-12-17	no assertion criteria provided	case-control