ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs147841035
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000697092 SCV000825683 benign Adams-Oliver syndrome 5 2023-09-27 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 2022-03-23 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.

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