ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.2734C>T (p.Arg912Trp) (rs201620358)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000250404 SCV000319466 uncertain significance Cardiovascular phenotype 2017-03-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Blueprint Genetics RCV000143938 SCV000188816 likely benign Thoracic aortic aneurysm and aortic dissection 2014-01-29 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000143938 SCV000902090 likely benign Thoracic aortic aneurysm and aortic dissection 2016-11-08 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc RCV000660154 SCV000782148 likely benign Connective tissue disorder 2016-11-01 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000608304 SCV000734678 likely benign Aortic valve disorder no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727058 SCV000705259 uncertain significance not provided 2017-01-04 criteria provided, single submitter clinical testing
GeneDx RCV000121671 SCV000513944 uncertain significance not specified 2017-04-21 criteria provided, single submitter clinical testing The R912W variant of uncertain significance in the NOTCH1 gene has previously been reported in a 52 year-old male with an aortic root aneurysm and bicuspid aortic valve (Ziganshin et al., 2015). This variant has also been reported in 5 unrelated Dutch individuals with left-sided congenital heart defects; one individual with a bicuspid aortic valve, one individual with aortic valve stenosis, and three individuals with coarctation of the aorta (Kerstjens-Frederikse et al., 2016). For one of the individuals with coarctation of the aorta, this variant was also found in the father who had a bicuspid aortic valve; segregation studies for the remaining four individuals were either not completed or non-informative (Kerstjens-Frederikse et al., 2016). R912W was observed in approximately 0.3% of alleles from individuals of European (Non-Finnish) ancestry and 0.2% of alleles from individuals of both Latino and European (Finnish) ancestry in the Exome Aggregation Consortium, indicating it may be a rare benign variant in these populations (Lek et al., 2016). Furthermore, this substitution occurs at a position that is not conserved across species. Nevertheless, R912W 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. In silico analysis predicts this variant is probably damaging to the protein structure/function.
ITMI RCV000121671 SCV000085869 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000227340 SCV000290256 likely benign Adams-Oliver syndrome 5 2017-12-14 criteria provided, single submitter clinical testing

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