Submissions for variant NM_017617.5(NOTCH1):c.4348G>A (p.Glu1450Lys)

gnomAD frequency: 0.00002  dbSNP: rs147841035

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697092	SCV000825683	benign	Adams-Oliver syndrome 5	2024-08-22	criteria provided, single submitter	clinical testing
GeneDx	RCV001547938	SCV001767761	uncertain significance	not provided	2018-10-25	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID 575010; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 28492532)
Genome-Nilou Lab	RCV000697092	SCV002553423	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270968	SCV002553424	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002332463	SCV002631047	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-10-07	criteria provided, single submitter	clinical testing	The p.E1450K variant (also known as c.4348G>A), located in coding exon 25 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 4348. The glutamic acid at codon 1450 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. 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	RCV003403619	SCV004121919	uncertain significance	not specified	2023-10-19	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.4348G>A (p.Glu1450Lys) results in a conservative amino acid change located in the Notch domain (IPR000800) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 244740 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4348G>A 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 and classified this variant as uncertain significance (n=3) and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.