Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001052417 | SCV001216627 | likely pathogenic | Adams-Oliver syndrome 5 | 2023-10-14 | 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. 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. |
Prevention |
RCV003413856 | SCV004115660 | likely pathogenic | NOTCH1-related condition | 2023-05-04 | criteria provided, single submitter | 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 individual 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 (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. |