ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.6814C>T (p.Arg2272Cys) (rs752505638)

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Total submissions: 4
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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 disease 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 uncertain significance Adams-Oliver syndrome 5 2019-05-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2272 of the NOTCH1 protein (p.Arg2272Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs752505638, ExAC 0.009%). This variant has not been reported in the literature in individuals with NOTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 391531). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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