Submissions for variant NM_017617.5(NOTCH1):c.5019-6G>A

gnomAD frequency: 0.00009  dbSNP: rs978561896

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000442898	SCV000533626	likely benign	not specified	2017-11-14	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472071	SCV000559933	likely benign	Adams-Oliver syndrome 5	2024-12-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798813	SCV002043530	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-05-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000472071	SCV002554342	likely benign	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270449	SCV002554343	likely benign	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003736771	SCV004563065	likely benign	not provided	2023-03-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000442898	SCV005205265	benign	not specified	2024-06-26	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.5019-6G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.3e-05 in 247122 control chromosomes (gnomAD). The observed variant frequency is approximately 150-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.5019-6G>A 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: 390720). Based on the evidence outlined above, the variant was classified as benign.