ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.4627G>A (p.Gly1543Arg)

gnomAD frequency: 0.00001  dbSNP: rs533102436
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001767197 SCV001991080 uncertain significance not provided 2022-12-22 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign in association with a Adams-Oliver syndrome (AOS) to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33536367)
Labcorp Genetics (formerly Invitae), Labcorp RCV002538797 SCV003457652 uncertain significance Adams-Oliver syndrome 5 2023-07-07 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1543 of the NOTCH1 protein (p.Gly1543Arg). 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NOTCH1 protein function. ClinVar contains an entry for this variant (Variation ID: 1306244). This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. This variant is present in population databases (rs533102436, gnomAD 0.02%).
Ambry Genetics RCV004641681 SCV005142235 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2024-05-07 criteria provided, single submitter clinical testing The c.4627G>A (p.G1543R) alteration is located in exon 26 (coding exon 26) of the NOTCH1 gene. This alteration results from a G to A substitution at nucleotide position 4627, causing the glycine (G) at amino acid position 1543 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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