ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs752505638
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Total submissions: 7
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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
Invitae 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.

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