Submissions for variant NM_017617.5(NOTCH1):c.4049G>T (p.Arg1350Leu) (rs150343794)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000474130	SCV000559902	likely benign	Adams-Oliver syndrome 5	2019-12-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000121687	SCV000569024	uncertain significance	not specified	2017-03-09	criteria provided, single submitter	clinical testing	The R1350L variant was first reported in a 70-year-old individual with a personal and family history of bicuspid aortic valve disease and thoracic aortic aneurysm, who also harbored a second missense variant in the NOTCH1 gene (McKellar at al., 2007). The R1350L variant has also been identified in a European American individual with aortic valve stenosis (McBride et al., 2008). However, no segregation studies were described in either of these publications. Kerstjens-Frederikse et al. (2016) subsequently reported R1350L in three individuals from a cohort of 428 Dutch individuals with non-syndromic left-sided congenital heart defects, and their individual phenotypes included hypoplastic left heart syndrome, coarctation of the aorta, and interruption of the aorta with a ventricular septal defect. In two of these cases, where parental testing was performed, R1350L was inherited from a father with a normal echocardiogram (Kerstjens-Frederikse et al., 2016).The R1350L 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. Moreover, this substitution occurs at a position that is conserved in mammals. Nevertheless, in silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, the R1350L variant has been observed in 54/48172 (0.11%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, this variant has been reported in other small control populations at a frequency of approximately 0.07-0.53% (McKellar et al., 2007; McBride et al., 2008; Bodian et al., 2014).
Ambry Genetics	RCV000621899	SCV000739359	likely benign	Cardiovascular phenotype	2019-01-09	criteria provided, single submitter	clinical testing	In silico models in agreement (benign);No disease association in small case-control study
Center for Human Genetics, Inc,Center for Human Genetics, Inc	RCV000680588	SCV000808012	likely benign	Connective tissue disease	2018-06-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000770629	SCV000902080	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-04-21	criteria provided, single submitter	clinical testing
ITMI	RCV000121687	SCV000085885	not provided	not specified	2013-09-19	no assertion provided	reference population