Submissions for variant NM_017617.5(NOTCH1):c.4985G>A (p.Arg1662Gln)

gnomAD frequency: 0.00001  dbSNP: rs774808496

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768033	SCV000898860	uncertain significance	Aortic valve disease 1; Adams-Oliver syndrome 5		criteria provided, single submitter	clinical testing	NOTCH1 NM_017617.5 exon 26 p.Arg1662Gln (c.4985G>A): This variant has not been reported in the literature and is not present in large control databases. This variant amino acid Glutamine (Gln) is present in several species, including multiple mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain
Labcorp Genetics (formerly Invitae), Labcorp	RCV001869058	SCV002142255	uncertain significance	Adams-Oliver syndrome 5	2024-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1662 of the NOTCH1 protein (p.Arg1662Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 625987). 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 95%. 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.
Genome-Nilou Lab	RCV001869058	SCV002553377	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002271020	SCV002553378	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702558	SCV001927846	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001702558	SCV001963700	likely benign	not provided		no assertion criteria provided	clinical testing