Submissions for variant NM_017617.5(NOTCH1):c.6521A>G (p.Lys2174Arg)

gnomAD frequency: 0.00004  dbSNP: rs761602495

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002310951	SCV000319614	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-12-12	criteria provided, single submitter	clinical testing	The p.K2174R variant (also known as c.6521A>G), located in coding exon 34 of the NOTCH1 gene, results from an A to G substitution at nucleotide position 6521. The lysine at codon 2174 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, arginine is the reference amino acid in other 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 alteration remains unclear.
GeneDx	RCV000493215	SCV000582567	uncertain significance	not provided	2023-04-14	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign in association with a NOTCH1-related disorder to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24113472, 28377411)
Invitae	RCV000692256	SCV000820070	benign	Adams-Oliver syndrome 5	2023-06-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000766054	SCV000897510	uncertain significance	Aortic valve disease 1; Adams-Oliver syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000692256	SCV002553298	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270161	SCV002553299	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002270161	SCV002761413	uncertain significance	Aortic valve disease 1	2021-03-31	criteria provided, single submitter	clinical testing	The NOTCH1 c.6521A>G variant is classified as VUS (PM2) Arginine is observed at this location in many mammals so likely to be tolerated.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000493215	SCV001954830	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000493215	SCV001964828	likely benign	not provided		no assertion criteria provided	clinical testing