Submissions for variant NM_017617.5(NOTCH1):c.6814C>T (p.Arg2272Cys)

gnomAD frequency: 0.00002  dbSNP: rs752505638

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000440204	SCV000534619	uncertain significance	not provided	2016-12-12	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the NOTCH1 gene. The R2272C variant has not beenpublished as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observedin approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. In addition, the R2272C variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differin polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position that is conservedacross species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.Nonetheless, this variant lacks observation in a significant number of affected individuals, segregation data, andfunctional evidence, all of which would further clarify pathogenicity.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.This result cannot be interpreted for diagnosis or used for family member screening at this time.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000680580	SCV000808000	uncertain significance	Connective tissue disorder	2018-06-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170918	SCV001333566	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-01-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001209653	SCV001381098	benign	Adams-Oliver syndrome 5	2023-02-16	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001209653	SCV002553276	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270469	SCV002553277	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001170918	SCV002664708	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-07-19	criteria provided, single submitter	clinical testing	The p.R2272C variant (also known as c.6814C>T), located in coding exon 34 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 6814. The arginine at codon 2272 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a neurodevelopmental disorder (NDD) cohort; however, clinical details were limited and additional alterations were identified in other associated genes (Wang T et al. J Genet Genomics, 2021 04;48:312-323). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.