Submissions for variant NM_017617.5(NOTCH1):c.839A>G (p.Asn280Ser)

gnomAD frequency: 0.00017  dbSNP: rs367825691

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000471470	SCV000548962	benign	Adams-Oliver syndrome 5	2024-01-11	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764821	SCV000895972	uncertain significance	Aortic valve disease 1; Adams-Oliver syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV002253448	SCV002525299	uncertain significance	not provided	2022-06-02	criteria provided, single submitter	clinical testing	Reported in a family with aortic coarctation and thickened aortic valve (Kerstjens-Frederikse et al., 2016), however complete clinical and segregation information was not provided; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26820064, 34426522)
Genome-Nilou Lab	RCV000471470	SCV002553979	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270509	SCV002553980	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002436431	SCV002679784	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-10-05	criteria provided, single submitter	clinical testing	The p.N280S variant (also known as c.839A>G), located in coding exon 5 of the NOTCH1 gene, results from an A to G substitution at nucleotide position 839. The asparagine at codon 280 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in congenital heart disease and sudden infant death cohorts (Kerstjens-Frederikse WS et al. Genet Med, 2016 09;18:914-23; Neubauer J et al. Eur J Hum Genet, 2017 04;25:404-409). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	RCV003330695	SCV004039543	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.839A>G (p.Asn280Ser) results in a conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 246648 control chromosomes. The observed variant frequency is approximately 168.66 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. c.839A>G has been reported in the literature in individuals affected with coarctation of the aorta (Kerstjens-Frederikse_2016), SIDS (Neubauer_2017), and sporadic bicuspid aortic valve (Debiec_2022), without strong evidence for causality. These reports do 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 publications have been ascertained in the context of this evaluation (PMID: 35288444, 26820064, 28074886). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: four classified the variant as VUS while one classified the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign.