ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.6733G>A (p.Gly2245Arg) (rs201613894)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000121701 SCV000536618 uncertain significance not specified 2017-02-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NOTCH1 gene. The G2245R variant has been previously reported to occur in 0.15% of alleles from an ancestrally diverse cohort of 681 healthy individuals from 352 families who underwent cancer-susceptibility genetic testing (Bodian et al., 2014). However, follow-up clinical evaluations, family histories and segregation studies were not described for these individuals harboring the G2245R variant. Additionally, the G2245R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G2245R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function.
Invitae RCV000539993 SCV000659485 uncertain significance Adams-Oliver syndrome 5 2019-05-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 2245 of the NOTCH1 protein (p.Gly2245Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs201613894, ExAC 0.07%) but has not been reported in the literature in individuals with a NOTCH1-related disease. ClinVar contains an entry for this variant (Variation ID: 134951). 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 tolerated, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000660177 SCV000782171 likely benign Connective tissue disease 2016-11-01 criteria provided, single submitter clinical testing
ITMI RCV000121701 SCV000085899 not provided not specified 2013-09-19 no assertion provided reference population

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