Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001855849 | SCV002120782 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2024-08-04 | 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 813 of the RET protein (p.Arg813Trp). This variant is present in population databases (rs779996040, gnomAD 0.005%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 12214285, 12865274, 30031151). ClinVar contains an entry for this variant (Variation ID: 599633). 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 | RCV004944137 | SCV005490966 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-07-03 | criteria provided, single submitter | clinical testing | The p.R813W variant (also known as c.2437C>T), located in coding exon 14 of the RET gene, results from a C to T substitution at nucleotide position 2437. The arginine at codon 813 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in patients with sporadic Hirschsprung disease (Lantieri F et al. Ann Hum Genet, 2006 Jan;70:12-26; Virtanen VB et al. Eur J Med Genet, 2019 Apr;62:229-234). This amino acid position is highly 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. |
| Human Genomics Unit, |
RCV000736277 | SCV000864575 | likely pathogenic | Aganglionic megacolon | 2013-01-01 | no assertion criteria provided | research | |
| Prevention |
RCV004740441 | SCV005357983 | uncertain significance | RET-related disorder | 2024-03-12 | no assertion criteria provided | clinical testing | The RET c.2437C>T variant is predicted to result in the amino acid substitution p.Arg813Trp. This variant has been reported in the heterozygous state in an individual with Hirschsprung disease (HSCR) characterized by rectosigmoid aganglionosis (Virtanen et al. 2019. PubMed ID: 30031151, Table 1). This variant has also been reported in an unaffected father and a child with HSCR (Griseri et al. 2002. PubMed ID: 12214285, Family 1). Alternate nucleotide changes affecting the same amino acid (p.Arg813Gln and p.Arg813Leu) have also been reported in individuals with RET-related phenotypes however, pathogenicity has not been conclusively established (Auricchio et al. 1999. PubMed ID: 10090908; Chatterjee. 2012. PubMed ID: 22729463; Jannot et al. 2012. PubMed ID: 22395866). This variant is reported in 0.0049% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |