Submissions for variant NM_017617.5(NOTCH1):c.4010C>G (p.Pro1337Arg)

gnomAD frequency: 0.00001  dbSNP: rs1043832212

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481924	SCV000572747	uncertain significance	not provided	2025-01-31	criteria provided, single submitter	clinical testing	Identified in a proband from a Heritable Thoracic Aortic Aneurysms or Dissections (HTAD) cohort in the published literature (PMID: 32748548); 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: 32748548)
Ambry Genetics	RCV002313255	SCV000739505	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-07-05	criteria provided, single submitter	clinical testing	The p.P1337R variant (also known as c.4010C>G), located in coding exon 24 of the NOTCH1 gene, results from a C to G substitution at nucleotide position 4010. The proline at codon 1337 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in a hereditable thoracic aortic aneurysm cohort; however, clinical details were limited (Musfee FI et al. Mol Genet Genomic Med, 2020 10;8:e1406). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000655253	SCV000777183	uncertain significance	Adams-Oliver syndrome 5	2024-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1337 of the NOTCH1 protein (p.Pro1337Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 423102). 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000481924	SCV002503111	uncertain significance	not provided	2021-12-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000655253	SCV002553450	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270582	SCV002553451	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing