ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.3556G>A (p.Glu1186Lys)

gnomAD frequency: 0.00001  dbSNP: rs1013688544
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002454895 SCV002617333 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2021-06-22 criteria provided, single submitter clinical testing The p.E1186K variant (also known as c.3556G>A), located in coding exon 22 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 3556. The glutamic acid at codon 1186 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV004529129 SCV004108666 uncertain significance NOTCH1-related disorder 2023-07-02 criteria provided, single submitter clinical testing The NOTCH1 c.3556G>A variant is predicted to result in the amino acid substitution p.Glu1186Lys. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Labcorp Genetics (formerly Invitae), Labcorp RCV003748378 SCV004407088 uncertain significance Adams-Oliver syndrome 5 2023-01-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1186 of the NOTCH1 protein (p.Glu1186Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1732634). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NOTCH1 protein function. 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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