ClinVar Miner

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

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Total submissions: 2
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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.
Invitae RCV001366341 SCV001562642 uncertain significance Adams-Oliver syndrome 5 2020-04-23 criteria provided, single submitter clinical testing This sequence change replaces leucine with methionine at codon 1848 of the NOTCH1 protein (p.Leu1848Met). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and methionine. This variant is present in population databases (rs35652719, ExAC 0.01%). This variant has not been reported in the literature in individuals with NOTCH1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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.

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