ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.383G>A (p.Arg128His)

gnomAD frequency: 0.00019  dbSNP: rs754086897
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000430313 SCV000535817 uncertain significance not provided 2018-08-16 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NOTCH1 gene. The R128H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the R128H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species and where histidine is the wild type in several species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp RCV000558664 SCV000659432 likely benign Adams-Oliver syndrome 5 2024-02-05 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000558664 SCV002554014 uncertain significance Adams-Oliver syndrome 5 2022-03-15 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002270484 SCV002554015 uncertain significance Aortic valve disease 1 2022-03-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV004649152 SCV005142126 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2024-03-28 criteria provided, single submitter clinical testing The p.R128H variant (also known as c.383G>A), located in coding exon 3 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 383. The arginine at codon 128 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.

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