Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001052417 | SCV001216627 | likely pathogenic | Adams-Oliver syndrome 5 | 2024-02-03 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 143 of the NOTCH1 protein (p.Pro143Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of NOTCH1-related conditions (PMID: 30582441, 34328347; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 848622). 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 not expected to disrupt NOTCH1 protein function with a negative predictive value of 95%. 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. |
| Gene |
RCV004590062 | SCV005081512 | uncertain significance | not provided | 2023-12-09 | criteria provided, single submitter | clinical testing | Identified in at least one patient with tetralogy of Fallot, although detailed clinical and segregation information was not provided (PMID: 30582441); 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; This variant is associated with the following publications: (PMID: 34328347, 35288444, 30582441) |
| Prevention |
RCV004536101 | SCV004115660 | likely pathogenic | NOTCH1-related disorder | 2024-07-09 | no assertion criteria provided | clinical testing | The NOTCH1 c.428C>T variant is predicted to result in the amino acid substitution p.Pro143Leu. This variant has been reported in three individuals with tetralogy of Fallot (Table S2, Page et al. 2019. PubMed ID: 30582441). This variant has been confirmed de novo in and individual with features of NOTCH1-associated disease (Internal Data, PreventionGenetics, LLC). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. |