Submissions for variant NM_017617.5(NOTCH1):c.2558_2560del (p.Phe853del)

dbSNP: rs779164170

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522624	SCV000620397	uncertain significance	not provided	2021-11-22	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In-frame deletion of one amino acid in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 451668; Landrum et al., 2016)
Invitae	RCV000803586	SCV000943465	uncertain significance	Adams-Oliver syndrome 5	2024-01-01	criteria provided, single submitter	clinical testing	This variant, c.2558_2560del, results in the deletion of 1 amino acid(s) of the NOTCH1 protein (p.Phe853del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs779164170, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 451668). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV000803586	SCV002553545	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270631	SCV002553546	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002431488	SCV002742992	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-09-20	criteria provided, single submitter	clinical testing	The c.2558_2560delTCT variant (also known as p.F853del) is located in coding exon 16 of the NOTCH1 gene. This variant results from an in-frame TCT deletion at nucleotide positions 2558 to 2560. This results in the in-frame deletion of a phenylalanine at codon 853. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488652	SCV004241287	likely benign	not specified	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.2558_2560delTCT (p.Phe853del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2.9e-05 in 1612802 control chromosomes, predominantly at a frequency of 3.7e-05 within the Non-Finnish European subpopulation in the gnomAD database (gnomAD v4.0.0). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Aortic Valve Disease phenotype (3.1e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.2558_2560delTCT in individuals affected with Aortic Valve Disease and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.