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

gnomAD frequency: 0.00223  dbSNP: rs201620358

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	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: seen in unaffected individuals, 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	2024-06-01	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