ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.5542C>A (p.Leu1848Met)

gnomAD frequency: 0.00004  dbSNP: rs35652719
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Johns Hopkins Genomics, Johns Hopkins University RCV001353368 SCV001548526 uncertain significance Aortic valve disease 1 2021-02-27 criteria provided, single submitter clinical testing This NOTCH1 variant (rs35652719) is rare (<0.1%) in a large population dataset (gnomAD: 5/278682 total alleles, 0.002%, no homozygotes) and has not been reported previously in ClinVar nor the literature to our knowledge. Of three bioinformatics tools queried, two predict that p.Leu1848Met would be damaging, while another predicts that this substitution would be tolerated. The leucine residue at this position is strongly conserved across all vertebrate species assessed. This variant is not predicted to affect normal exon 30 splicing, although this has not been confirmed experimentally to our knowledge. Due to insufficient evidence, we consider the clinical significance of c.5542C>A to be uncertain at this time.
Labcorp Genetics (formerly Invitae), Labcorp RCV001366341 SCV001562642 benign Adams-Oliver syndrome 5 2022-08-16 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001366341 SCV002553338 uncertain significance Adams-Oliver syndrome 5 2022-03-15 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001353368 SCV002553339 uncertain significance Aortic valve disease 1 2022-03-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV005372669 SCV006035522 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2025-02-27 criteria provided, single submitter clinical testing The p.L1848M variant (also known as c.5542C>A), located in coding exon 30 of the NOTCH1 gene, results from a C to A substitution at nucleotide position 5542. The leucine at codon 1848 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

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