Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001379274 | SCV001577045 | likely pathogenic | Multiple endocrine neoplasia, type 2 | 2021-04-09 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 330 of the RET protein (p.Arg330Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant has been observed in individuals and families with Hirschsprung disase (PMID: 7633441, 8114939, 7581377). ClinVar contains an entry for this variant (Variation ID: 13926). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to affect RET protein function (PMID: 8894691). |
| All of Us Research Program, |
RCV001379274 | SCV004817287 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2023-02-22 | criteria provided, single submitter | clinical testing | The variant has been reported in patients affected with AD Hirschsprung disease. |
| Clinical Genetics Laboratory, |
RCV004696636 | SCV005198055 | likely pathogenic | not provided | 2022-05-27 | criteria provided, single submitter | clinical testing | |
| Neuberg Centre For Genomic Medicine, |
RCV000014951 | SCV005849412 | likely pathogenic | Hirschsprung disease, susceptibility to, 1 | 2023-06-22 | criteria provided, single submitter | clinical testing | The observed missense variant c.989G>A(p.Arg330Gln) in RET gene has been reported previously in individuals with Hirschsprung disease (Pelet A, et al., 2005, Edery P, et al., 1994). Experimental studies have shown that this missense change affects RET function, however, available evidence is insufficient to prove pathogenicity (Iwashita T, 1996). This variant is absent in gnomAD Exomes. It has been submitted to ClinVar as Likely Pathogenic/ risk factor. The amino acid Arg at position 330 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence (Polyphen-Probably damaging, SIFT-Tolerated and MutationTaster-disease causing) predicts conflicting evidence on protein structure and function for this variant.The reference amino acid p.Arg330Gln in RET is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. |
| OMIM | RCV000014951 | SCV000035207 | risk factor | Hirschsprung disease, susceptibility to, 1 | 1994-01-27 | no assertion criteria provided | literature only |