Submissions for variant NM_017617.5(NOTCH1):c.6083-4G>A

gnomAD frequency: 0.00008  dbSNP: rs570242146

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000609160	SCV000716373	likely benign	not specified	2017-03-01	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	RCV002062991	SCV002412149	likely benign	Adams-Oliver syndrome 5	2023-11-07	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002062991	SCV002553901	benign	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270741	SCV002553903	benign	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000609160	SCV004223390	benign	not specified	2023-11-06	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.6083-4G>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 4.4e-05 in 248916 control chromosomes, predominantly at a frequency of 8.9e-05 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 142 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 phenotype (6.3e-07), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.6083-4G>A has been reported in the literature in at least one individual affected with thoracic aortic aneurysm/dissection (e.g., Renner_2019), however without strong evidence for causality (e.g., lack of co-segregation data.) This report therefore does not provide unequivocal conclusions about association of the variant with Adams-Oliver Syndrome 5. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 30675029). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV004024916	SCV005027342	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2024-01-24	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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001580037	SCV001809443	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001580037	SCV001967215	likely benign	not provided		no assertion criteria provided	clinical testing