Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001797960 | SCV002041845 | uncertain significance | not specified | 2021-11-30 | criteria provided, single submitter | clinical testing | Variant summary: UNC13D c.2672T>C (p.Leu891Pro) results in a non-conservative amino acid change located in the MUN domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-06 in 165568 control chromosomes. c.2672T>C has been reported in the literature in individuals affected with Familial Hemophagocytic Lymphohistiocytosis (Stadt_2006, Elstak_2012). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Labcorp Genetics |
RCV001868903 | SCV002183203 | likely pathogenic | Familial hemophagocytic lymphohistiocytosis 3 | 2024-02-12 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 891 of the UNC13D protein (p.Leu891Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 16278825, 21755595; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1329069). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt UNC13D protein function with a positive predictive value of 80%. 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. |
| Institute of Human Genetics, |
RCV002222265 | SCV002499708 | uncertain significance | See cases | 2022-02-09 | criteria provided, single submitter | clinical testing | ACMG categories: PM2,PP3 |