Submissions for variant NM_001114753.3(ENG):c.1267A>C (p.Asn423His)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV005117475	SCV005736192	likely pathogenic	Hereditary hemorrhagic telangiectasia	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 423 of the ENG protein (p.Asn423His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary hemorrhagic telangiectasia (Invitae). 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 ENG protein function with a positive predictive value of 95%. This variant disrupts the p.Asn423 amino acid residue in ENG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32573726, 34872578). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.