ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.4238G>A (p.Arg1413His) (rs371068504)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000248136 SCV000320436 uncertain significance Cardiovascular phenotype 2015-11-13 criteria provided, single submitter clinical testing The p.R1413H variant (also known as c.4238G>A), located in coding exon 25 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 4238. The arginine at codon 1413 is replaced by histidine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs371068504. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/12068) total alleles studied and 0.01% (1/8224) European American alleles. Allele frequency data for this nucleotide position is not currently available from the 1000 Genomes Project. 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 variant remains unclear.
Invitae RCV000471799 SCV000548959 uncertain significance Adams-Oliver syndrome 5 2020-09-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1413 of the NOTCH1 protein (p.Arg1413His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs371068504, ExAC 0.009%). This variant has not been reported in the literature in individuals with NOTCH1-related disease. ClinVar contains an entry for this variant (Variation ID: 264469). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Fulgent Genetics,Fulgent Genetics RCV000766060 SCV000897516 uncertain significance Aortic valve disease 1; Adams-Oliver syndrome 5 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV001536590 SCV001753369 uncertain significance not provided 2019-12-27 criteria provided, single submitter clinical testing Has not been previously published in association with NOTCH1-related disorders to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 264469; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28682882)

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