Submissions for variant NM_017617.5(NOTCH1):c.5018+13C>T

gnomAD frequency: 0.00008  dbSNP: rs752508890

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000426235	SCV000536000	likely benign	not specified	2017-01-05	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.
Invitae	RCV002056672	SCV002391389	likely benign	Adams-Oliver syndrome 5	2024-01-02	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002056672	SCV002554352	likely benign	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270488	SCV002554353	likely benign	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002488982	SCV002801559	likely benign	Aortic valve disease 1; Adams-Oliver syndrome 5	2021-09-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000426235	SCV004803486	benign	not specified	2024-01-02	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.5018+13C>T alters a conserved nucleotide located at a position not widely known to affect splicing. 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 4.9e-05 in 1497318 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 79.075 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 benign. To our knowledge, no occurrence of c.5018+13C>T in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited 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.