ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.2636G>A (p.Arg879Gln)

gnomAD frequency: 0.00010  dbSNP: rs368011392
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000476977 SCV000548917 benign Adams-Oliver syndrome 5 2024-01-08 criteria provided, single submitter clinical testing
GeneDx RCV000523567 SCV000621033 uncertain significance not provided 2018-05-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NOTCH1 gene. The R879Q variant has been reported as a variant of uncertain significance in one patient with aortopathy (Yang et al., 2016). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R879Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species and where glutamine (Q) is present as the wild type in at least one species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Genome-Nilou Lab RCV000476977 SCV002553539 uncertain significance Adams-Oliver syndrome 5 2022-03-15 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002270495 SCV002553540 uncertain significance Aortic valve disease 1 2022-03-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV002451109 SCV002740000 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2022-06-03 criteria provided, single submitter clinical testing The p.R879Q variant (also known as c.2636G>A), located in coding exon 17 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 2636. The arginine at codon 879 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a congenital heart defect cohort (Kerstjens-Frederikse WS et al. Genet Med, 2016 09;18:914-23). 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic RCV000523567 SCV004225189 uncertain significance not provided 2022-10-11 criteria provided, single submitter clinical testing BP4, PP2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000523567 SCV004563226 uncertain significance not provided 2023-04-26 criteria provided, single submitter clinical testing The NOTCH1 c.2636G>A; p.Arg879Gln variant (rs368011392) is reported in the literature in an individual affected with hypoplastic left heart syndrome (Kerstjens-Frederikse 2016). This variant is reported in ClinVar (Variation ID: 409039) and is found in the general population with an overall allele frequency of 0.0091% (25/274,500 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.213). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Kerstjens-Frederikse WS et al. Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD and their families. Genet Med. 2016 Sep;18(9):914-23. PMID: 26820064.

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