Submissions for variant NM_017617.5(NOTCH1):c.2542G>A (p.Glu848Lys)

gnomAD frequency: 0.00318  dbSNP: rs35136134

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000121669	SCV000226515	likely benign	not specified	2017-04-14	criteria provided, single submitter	clinical testing
Invitae	RCV000229399	SCV000290251	benign	Adams-Oliver syndrome 5	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001170158	SCV000319434	benign	Familial thoracic aortic aneurysm and aortic dissection	2017-06-01	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000121669	SCV000532483	benign	not specified	2016-10-10	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660152	SCV000782146	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170158	SCV001332708	benign	Familial thoracic aortic aneurysm and aortic dissection	2017-12-07	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000229399	SCV002554934	benign	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002269850	SCV002554935	benign	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003227670	SCV003924135	likely benign	Aortic valve disease 1; Adams-Oliver syndrome 5	2021-03-30	criteria provided, single submitter	clinical testing	NOTCH1 NM_017617.4 exon 16 p.Glu848Lys (c.2542G>A): This variant has been reported in the literature in one individual with suspected hereditary thoracic arotic disease (Overwater 2018 PMID:29907982). However, his variant is also present in 0.6% (83/13660) of Latino alleles in the Genome Aggregation Database, including 2 homozygotes in the European population (https://gnomad.broadinstitute.org/variant/9-136511197-C-T?dataset=gnomad_r3) and is present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:134919). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121669	SCV004029502	likely benign	not specified	2023-07-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001573939	SCV004162046	benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	NOTCH1: BS1, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001573939	SCV004564666	likely benign	not provided	2023-11-10	criteria provided, single submitter	clinical testing
ITMI	RCV000121669	SCV000085867	not provided	not specified	2013-09-19	no assertion provided	reference population
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573939	SCV001800533	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001573939	SCV001806907	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001573939	SCV001927506	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000121669	SCV001951510	benign	not specified		no assertion criteria provided	clinical testing