Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001855048 | SCV002181362 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2022-10-13 | criteria provided, single submitter | clinical testing | 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. Experimental studies have shown that this missense change affects RET function (PMID: 29601828). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 274004). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 7704557, 29601828). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 399 of the RET protein (p.Pro399Leu). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002469092 | SCV002766429 | uncertain significance | not specified | 2022-11-16 | criteria provided, single submitter | clinical testing | Variant summary: RET c.1196C>T (p.Pro399Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251002 control chromosomes. c.1196C>T has been reported in the literature in individuals affected with features of Hirschsprung Disease (HSPR) (example, Sribudiani_2018, Kuil_2021, Yin_1994). One of these studies reported a large multigenerational family in which the variant was transmitted to 4 HSPR affected family members and one family member reportedly affected with "functional constipation" but not diagnosed as HSPR. Additionally, one HSPR affected family member did not carry this variant, demonstrating incomplete segregation with disease (Sribudiani_2018). The authors proposed the presence of a risk haplotype contributing to the disease by "enhancing" the penetrance of this RET variant. Furthermore, putative variants in other genes were reported to underlie the pathogenesis in the HSPR affected family member who did not carry this variant. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating disturbed protein glycosylation and impaired phosphorylation upon GNDF activation in-vitro (example, Sribudiani_2018). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, given the multifactorial etiology of disease reported in the evidence ascertained herein, the variant was classified as a VUS-possibly pathogenic risk factor for Hirschsprung Disease. |
| Clinical Genetics, |
RCV000508605 | SCV000328919 | pathogenic | Hirschsprung disease, susceptibility to, 1 | 2016-11-18 | no assertion criteria provided | clinical testing |