Submissions for variant NM_017617.5(NOTCH1):c.4168C>A (p.Pro1390Thr)

gnomAD frequency: 0.00061  dbSNP: rs191645600

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001798385	SCV000319755	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-01-20	criteria provided, single submitter	clinical testing	The p.P1390T variant (also known as c.4168C>A), located in coding exon 25 of the NOTCH1 gene, results from a C to A substitution at nucleotide position 4168. The proline at codon 1390 is replaced by threonine, an amino acid with highly similar properties. This variant was first described in two patients with bicuspid aortic valve and thoracic aortic aneurysm (McKellar et al. J Thorac Cardiovasc Surg. 2007;134(2):290-6; Girdauskas E. et al. Eur J Cardiothorac Surg. 2017;Apr:156-162). In addition, this variant has been reported in a newborn male with tetralogy of Fallot, pulmonic stenosis, and cryptorchidism (Ceyhan-Birsoy O et al. Am. J. Hum. Genet., 2019 Jan;104:76-93). This variant has also been seen in a whole genome sequencing cohort, but cardiovascular history was not provided (Bodian DL et al. PLoS ONE. 2014;9(4):e94554). This amino acid position is 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	RCV000525275	SCV000659441	likely benign	Adams-Oliver syndrome 5	2024-01-29	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660162	SCV000782156	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121685	SCV000966705	uncertain significance	not specified	2018-02-14	criteria provided, single submitter	clinical testing	The p.Pro1390Thr (NM_017617.3 c.4168C>A) variant in NOTCH1 has been reported in 2 individuals with bicuspid aortic valve disease (McKellar 2007 and Girdauskas 2 017), and has been identified in 0.1% (126/117,504) of European chromosomes by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs191645600). It has also been reported in ClinVar (Variation ID#134935). Comput ational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Pro1390Thr variant is uncertain.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV001836733	SCV001021975	uncertain significance	Heart, malformation of	2019-12-06	criteria provided, single submitter	clinical testing
GeneDx	RCV001562831	SCV001785661	likely benign	not provided	2020-09-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30609409, 28387797, 27059385, 23102684, 20497191, 17662764, 24728327)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798385	SCV002043520	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2020-01-17	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002055371	SCV002495877	uncertain significance	Aortic valve disease 1; Adams-Oliver syndrome 5	2021-03-30	criteria provided, single submitter	clinical testing	NOTCH1 NM_017617.4 exon 25 p.Pro1390Thr (c.4168C>A): This variant has been reported in the literature in two individuals with bicuspid aortic valve and aortic dilation, as well as in one neonate with TOF, pulmonic stenosis, and cryptorchidism (McKellar 2007 PMID:17662764, Girdauskas 2017 PMID:28387797, Ceyhan-Birsoy 2019 PMID:30609409). However, this variant is also present in 0.1% (72/68038) of European alleles in the Genome Aggregation Database, including one homozygote (https://gnomad.broadinstitute.org/variant/9-136505728-G-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:134935). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV001562831	SCV004162025	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	NOTCH1: BS1
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001562831	SCV004563204	likely benign	not provided	2023-10-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003945096	SCV004764315	likely benign	NOTCH1-related condition	2021-09-24	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
ITMI	RCV000121685	SCV000085883	not provided	not specified	2013-09-19	no assertion provided	reference population
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000121685	SCV001808508	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001562831	SCV001931656	likely benign	not provided		no assertion criteria provided	clinical testing