ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.5674G>A (p.Gly1892Arg)

gnomAD frequency: 0.00001  dbSNP: rs761427888
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
New York Genome Center RCV004799549 SCV001441459 uncertain significance Aortic valve disease 1; Adams-Oliver syndrome 5 2022-01-14 criteria provided, single submitter clinical testing The c.5674G>A (p.Gly1892Arg) variant identified in the NOTCH1 gene substitutes a very well conserved Glycine for Arginine at amino acid 1892/2556 (coding exon 31/34).This variant is found with low frequency in gnomAD (2 heterozygotes, 0 homozygotes; allele frequency:8.58e-6) suggesting it is not a common benign variant in the populations represented in this database. In silico algorithms predict this variant to be Deleterious (Provean; score:-6.40) and Damaging (SIFT; score:0.003) to the function of the canonical transcript. This variant is absent from ClinVar and to our current knowledge has not been reported in affected individuals in the literature. The p.Gly1892 residue is within the intracellular region of NOTCH1, although not within a mapped domain (UniProtKB: P46531). Given the lack of compelling evidence for its pathogenicity, the c.5674G>A (p.Gly1892Arg) variant identified in the NOTCH1 gene is reported here as a Variant of Uncertain Significance.
GeneDx RCV001577372 SCV001804733 uncertain significance not provided 2019-07-12 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab RCV002271201 SCV002553331 uncertain significance Adams-Oliver syndrome 5 2022-03-15 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002271200 SCV002553332 uncertain significance Aortic valve disease 1 2022-03-15 criteria provided, single submitter clinical testing

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