Submissions for variant NM_017617.5(NOTCH1):c.6481C>T (p.Pro2161Ser)

gnomAD frequency: 0.00003  dbSNP: rs201518848

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000727124	SCV000617310	uncertain significance	not provided	2023-08-11	criteria provided, single submitter	clinical testing	Reported in an individual with bicuspid aortic valve (Bonachea et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25260786, 31624253)
Eurofins Ntd Llc (ga)	RCV000727124	SCV000705953	uncertain significance	not provided	2017-03-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001058437	SCV001223010	benign	Adams-Oliver syndrome 5	2024-11-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001335846	SCV001529089	uncertain significance	Aortic valve disease 1	2018-04-20	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV001058437	SCV002553300	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001335846	SCV002553301	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002367728	SCV002660761	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-01-05	criteria provided, single submitter	clinical testing	The p.P2161S variant (also known as c.6481C>T), located in coding exon 34 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 6481. The proline at codon 2161 is replaced by serine, an amino acid with similar properties. This variant was identified in a cohort of individuals with bicuspid aortic valve and in an individual with heterotaxy (Bonachea EM et al. BMC Med Genomics, 2014 Sep;7:56; Watkins WS et al. Nat Commun. 2019 10;10(1):4722). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002481696	SCV002779589	uncertain significance	Aortic valve disease 1; Adams-Oliver syndrome 5	2022-04-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056116	SCV005726223	likely benign	not specified	2024-11-18	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.6481C>T (p.Pro2161Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 246054 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 176 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 phenotype (6.3e-07). To our knowledge, no occurrence of c.6481C>T in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 449324). Based on the evidence outlined above, the variant was classified as likely benign.
GenomeConnect - Invitae Patient Insights Network	RCV001535474	SCV001749401	not provided	Adams-Oliver syndrome 5; Aortic valve disorder		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 12-27-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.