ClinVar Miner

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

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001084013 SCV000290256 likely benign Adams-Oliver syndrome 5 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000250404 SCV000319466 likely benign Cardiovascular phenotype 2019-03-08 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727058 SCV000705259 uncertain significance not provided 2017-01-04 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000660154 SCV000782148 likely benign Connective tissue disease 2016-11-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000143938 SCV000902090 likely benign Familial thoracic aortic aneurysm and aortic dissection 2016-11-08 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV001027797 SCV001190407 uncertain significance Aortic valve disorder; Adams-Oliver syndrome 5 2019-04-15 criteria provided, single submitter clinical testing NOTCH1 NM_017617.5 exon 17 p.Arg912Trp (c.2734C>T): This variant has been reported in the literature in one individual with an aortic aneurysm and in five individuals with nonsyndromic congenital heart disease (bicuspid aortic valve, coarctation of the aorta, aortic valve stenosis) (Ziganshin 2015 PMID:26188975, Kerstijens-Frederikse 2016 PMID:26820064). However, this variant is also present in 0.2% (317/119414) of European alleles in the Genome Aggregation Database, including one homozygote (https://gnomad.broadinstitute.org/variant/9-139405111-G-A). This variant is present in ClinVar (Variation ID:134921). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
ITMI RCV000121671 SCV000085869 not provided not specified 2013-09-19 no assertion provided reference population
Blueprint Genetics RCV000143938 SCV000188816 likely benign Familial thoracic aortic aneurysm and aortic dissection 2014-01-29 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000608304 SCV000734678 likely benign Aortic valve disorder no assertion criteria provided clinical testing

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