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

dbSNP: rs150343794

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474130	SCV000559902	likely benign	Adams-Oliver syndrome 5	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001719887	SCV000569024	likely benign	not provided	2020-05-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17662764, 18593716, 24728327, 26820064)
Ambry Genetics	RCV000770629	SCV000739359	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-01-09	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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000680588	SCV000808012	likely benign	Connective tissue disorder	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
CeGaT Center for Human Genetics Tuebingen	RCV001719887	SCV004162027	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	NOTCH1: BS1
PreventionGenetics, part of Exact Sciences	RCV004542907	SCV004783999	likely benign	NOTCH1-related disorder	2021-12-15	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121687	SCV005203103	likely benign	not specified	2024-07-09	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.4049G>T (p.Arg1350Leu) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0006 in 220306 control chromosomes, predominantly at a frequency of 0.001 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1600 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 phenotype (6.3e-07). To our knowledge, no occurrence of c.4049G>T in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 134937). Based on the evidence outlined above, the variant was classified as likely benign.
ITMI	RCV000121687	SCV000085885	not provided	not specified	2013-09-19	no assertion provided	reference population