ClinVar Miner

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

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Total submissions: 6
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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

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