ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1423C>T (p.Arg475Trp)

gnomAD frequency: 0.00004  dbSNP: rs746512075
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000693492 SCV000821363 uncertain significance Multiple endocrine neoplasia, type 2 2024-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 475 of the RET protein (p.Arg475Trp). This variant is present in population databases (rs746512075, gnomAD 0.005%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 11955539). ClinVar contains an entry for this variant (Variation ID: 572175). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RET function (PMID: 20473317). 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.
Mendelics RCV000709109 SCV000838379 uncertain significance Multiple endocrine neoplasia type 2A 2018-07-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV001011519 SCV001171850 uncertain significance Hereditary cancer-predisposing syndrome 2024-04-16 criteria provided, single submitter clinical testing The p.R475W variant (also known as c.1423C>T), located in coding exon 7 of the RET gene, results from a C to T substitution at nucleotide position 1423. The arginine at codon 475 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been previously identified in an individual with sporadic Hirschsprung disease (Fitze G, et al. Lancet 2002 Apr; 359(9313):1200-5). Structural and functional analyses indicate that this alteration results in protein misfolding (Kjaer S, et al. Hum. Mol. Genet. 2003 Sep;12(17):2133-44; Kjaer S, et al. Nat. Struct. Mol. Biol. 2010 Jun; 17(6):726-31). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002499241 SCV002784619 uncertain significance Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A 2021-09-27 criteria provided, single submitter clinical testing
GeneDx RCV003159152 SCV003853137 uncertain significance not provided 2022-09-29 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; Published functional studies demonstrate secretion efficiency that surpassed wild-type in a quantitative cell-based RET maturation assay and was classified as fully rescuable (Kjaer et al., 2010); Observed in individuals with Hirschsprung disease (Fitze et al., 2002); This variant is associated with the following publications: (PMID: 11955539, 20473317, 14633923, 33193891)
All of Us Research Program, National Institutes of Health RCV000693492 SCV004830509 uncertain significance Multiple endocrine neoplasia, type 2 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 475 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). Functional studies have reported that this variant may have a partial or mild impact on RET protein misfolding via indirect proxy assays (PMID: 12915470, 20473317). This variant has not been reported in individuals affected with RET-related cancer in the literature. This variant has been identified in 6/282740 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 RCV004569318 SCV005054222 uncertain significance Hirschsprung disease, susceptibility to, 1 2023-12-07 criteria provided, single submitter clinical testing

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