ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.5414T>C (p.Leu1805Pro)

gnomAD frequency: 0.00010  dbSNP: rs201779159
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000594908 SCV000705654 uncertain significance not provided 2017-01-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV002315892 SCV000739441 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2020-10-12 criteria provided, single submitter clinical testing The p.L1805P variant (also known as c.5414T>C), located in coding exon 29 of the NOTCH1 gene, results from a T to C substitution at nucleotide position 5414. The leucine at codon 1805 is replaced by proline, an amino acid with similar properties. This alteration was reported in a bicuspid aortic valve cohort (Girdauskas E et al. Eur J Cardiothorac Surg, 2017 Jul;52:156-162). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000655262 SCV000777192 benign Adams-Oliver syndrome 5 2024-01-02 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000655262 SCV002553353 uncertain significance Adams-Oliver syndrome 5 2022-03-15 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002270717 SCV002553354 uncertain significance Aortic valve disease 1 2022-03-15 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004530694 SCV004119897 uncertain significance NOTCH1-related disorder 2023-06-22 criteria provided, single submitter clinical testing The NOTCH1 c.5414T>C variant is predicted to result in the amino acid substitution p.Leu1805Pro. This variant was reported in a study of individuals with bicuspid aortic valve-associated aortopathy, however additional details were not provided (Girdauskas et al. 2017. PubMed ID: 28387797; Girdauskas et al. 2018. PubMed ID: 30059548). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-139396511-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000594908 SCV004564189 uncertain significance not provided 2023-05-09 criteria provided, single submitter clinical testing The NOTCH1 c.5414T>C; p.Leu1805Pro variant (rs201779159) is reported in the literature in an individual affected with bicuspid aortic valve disease (Girdauskas 2017). This variant is reported in ClinVar (Variation ID: 499922) and if found in the non-Finnish European population with an allele frequency of 0.0109% (14/128,060 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.648). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Girdauskas E et al. Genetic abnormalities in bicuspid aortic valve root phenotype: preliminary results. Eur J Cardiothorac Surg. 2017 Jul 1;52(1):156-162. PMID: 28387797.
John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine RCV002285163 SCV002575044 uncertain significance Pulmonary arterial hypertension 2022-09-26 no assertion criteria provided clinical testing

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