Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000662983 | SCV000785968 | uncertain significance | Multiple endocrine neoplasia type 2A | 2018-02-16 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000704241 | SCV000833182 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2024-06-04 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 423 of the RET protein (p.Gly423Arg). This variant is present in population databases (rs767601598, gnomAD 0.003%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 21995290, 22174939). ClinVar contains an entry for this variant (Variation ID: 548849). 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 | RCV002369789 | SCV002685829 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-10-06 | criteria provided, single submitter | clinical testing | The p.G423R variant (also known as c.1267G>A), located in coding exon 7 of the RET gene, results from a G to A substitution at nucleotide position 1267. The glycine at codon 423 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in two individuals with Hirschsprung disease (So MT, PLoS ONE 2011 ; 6(12):e28986 and Núñez-Torres R, BMC Med. Genet. 2011 ; 12:138). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Gene |
RCV002464285 | SCV002759041 | uncertain significance | not provided | 2022-05-31 | 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; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may also impact gene splicing, but in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 21995290, 28179590, 24241536, 22174939) |
| All of Us Research Program, |
RCV000704241 | SCV004834088 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2023-08-28 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with arginine at codon 423 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Hirschsprung disease (PMID: 21995290, 22174939). This variant has been identified in 2/250476 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. |