ClinVar Miner

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

gnomAD frequency: 0.00223  dbSNP: rs201620358
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Total submissions: 19
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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 2024-01-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000143938 SCV000319466 likely benign Familial thoracic aortic aneurysm and aortic dissection 2019-03-08 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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.
Eurofins Ntd Llc (ga) 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 disorder 2016-11-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000143938 SCV000902090 benign Familial thoracic aortic aneurysm and aortic dissection 2020-01-27 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 disease 1; Adams-Oliver syndrome 5 2021-03-30 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.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000727058 SCV001448863 benign not provided 2016-07-29 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000727058 SCV001714336 uncertain significance not provided 2021-11-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121671 SCV003928455 likely benign not specified 2023-04-04 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000727058 SCV004162040 benign not provided 2023-09-01 criteria provided, single submitter clinical testing NOTCH1: PP2, BS1, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000727058 SCV004564168 uncertain significance not provided 2023-10-19 criteria provided, single submitter clinical testing The NOTCH1 c.2734C>T; p.Arg912Trp variant (rs201620358) is reported in the literature in individuals with aortic valve stenosis, aortic root aneurysm, bicuspid aortic valve, or coarctation of the aorta (Kerstjens-Frederikse 2016, Ziganshin 2015). Incomplete penetrance and variable expressivity are reported for NOTCH1 (Roifman 2021). This variant is also reported in ClinVar (Variation ID: 134921). This variant is found in the general population with an overall allele frequency of 0.18% (469/263284 alleles, including one homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.402). Based on the available information, the clinical significance of this variant is uncertain. References: Kerstjens-Frederikse WS et al. Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD and their families. Genet Med. 2016 Sep;18(9):914-23. PMID: 26820064. Roifman M et al. Heterozygous NOTCH1 deletion associated with variable congenital heart defects. Clin Genet. 2021 Jun;99(6):836-841. PMID: 33630301. Ziganshin BA et al. Routine Genetic Testing for Thoracic Aortic Aneurysm and Dissection in a Clinical Setting. Ann Thorac Surg. 2015 Nov;100(5):1604-11. PMID: 26188975.
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 disease 1 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000121671 SCV001807145 benign not specified no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000727058 SCV001927828 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000727058 SCV001955011 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000727058 SCV001968677 likely benign not provided no assertion criteria provided clinical testing

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