ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.4013C>T (p.Ala1338Val)

gnomAD frequency: 0.00003  dbSNP: rs1397249771
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002315078 SCV000739396 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2016-02-04 criteria provided, single submitter clinical testing The p.A1338V variant (also known as c.4013C>T), located in coding exon 24 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 4013. The alanine at codon 1338 is replaced by valine, an amino acid with 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 6031 samples (12062 alleles) with coverage at this position. This amino acid position is poorly 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.
Invitae RCV001307582 SCV001497000 uncertain significance Adams-Oliver syndrome 5 2023-11-02 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1338 of the NOTCH1 protein (p.Ala1338Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 520032). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
GeneDx RCV001770554 SCV001993811 uncertain significance not provided 2019-05-10 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Genome-Nilou Lab RCV001307582 SCV002553447 uncertain significance Adams-Oliver syndrome 5 2022-03-15 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002270878 SCV002553449 uncertain significance Aortic valve disease 1 2022-03-15 criteria provided, single submitter clinical testing

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