ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.775G>A (p.Asp259Asn)

gnomAD frequency: 0.00002  dbSNP: rs763187824
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002310968 SCV000319684 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2015-05-22 criteria provided, single submitter clinical testing The p.D259N variant (also known as c.775G>A), located in coding exon 5 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 775. The aspartic acid at codon 259 is replaced by asparagine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6246 samples (12492 alleles) with coverage at this position. This amino acid position is highly 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 variant remains unclear.
GeneDx RCV000523362 SCV000620987 uncertain significance not provided 2017-09-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NOTCH1 gene. The D259N variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The D259N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across most species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Fulgent Genetics, Fulgent Genetics RCV000764822 SCV000895973 uncertain significance Aortic valve disease 1; Adams-Oliver syndrome 5 2018-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001054792 SCV001219143 benign Adams-Oliver syndrome 5 2023-12-02 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001054792 SCV002553985 uncertain significance Adams-Oliver syndrome 5 2022-03-15 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002270168 SCV002553987 uncertain significance Aortic valve disease 1 2022-03-15 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004535224 SCV004114017 uncertain significance NOTCH1-related disorder 2022-08-26 criteria provided, single submitter clinical testing The NOTCH1 c.775G>A variant is predicted to result in the amino acid substitution p.Asp259Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-139413985-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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