Submissions for variant NM_017617.5(NOTCH1):c.5452C>G (p.Leu1818Val)

gnomAD frequency: 0.00001  dbSNP: rs1064796983

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484133	SCV000574279	uncertain significance	not provided	2017-03-20	criteria provided, single submitter	clinical testing	The L1818V variant has not been published as pathogenic or been reported as benign to our knowledge. The L1818V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved in mammals. Nevertheless, the L1818V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Lastly, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Ambry Genetics	RCV002313260	SCV000739407	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-04-05	criteria provided, single submitter	clinical testing	The p.L1818V variant (also known as c.5452C>G), located in coding exon 29 of the NOTCH1 gene, results from a C to G substitution at nucleotide position 5452. The leucine at codon 1818 is replaced by valine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6053 samples (12106 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Centre of Medical Genetics, University of Antwerp	RCV000662262	SCV000747186	uncertain significance	Adams-Oliver syndrome 5	2017-12-01	criteria provided, single submitter	research
Genome-Nilou Lab	RCV000662262	SCV002553346	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270583	SCV002553348	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000662262	SCV005774932	uncertain significance	Adams-Oliver syndrome 5	2024-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1818 of the NOTCH1 protein (p.Leu1818Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Adams-Oliver syndrome (PMID: 29924900). ClinVar contains an entry for this variant (Variation ID: 424467). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt NOTCH1 protein function with a negative predictive value of 80%. 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.
PreventionGenetics, part of Exact Sciences	RCV004541529	SCV004764300	uncertain significance	NOTCH1-related disorder	2023-10-19	no assertion criteria provided	clinical testing	The NOTCH1 c.5452C>G variant is predicted to result in the amino acid substitution p.Leu1818Val. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.