Submissions for variant NM_017617.5(NOTCH1):c.6130G>A (p.Ala2044Thr)

gnomAD frequency: 0.00003  dbSNP: rs544856644

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000242723	SCV000319447	uncertain significance	Cardiovascular phenotype	2015-02-09	criteria provided, single submitter	clinical testing	The p.A2044T variant (also known as c.6130G>A), located in coding exon 33 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 6130. The alanine at codon 2044 is replaced by threonine, an amino acid with some similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6,316 samples (12,632 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species, except threonine is the reference amino acid in lamprey. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001210978	SCV001382496	benign	Adams-Oliver syndrome 5	2025-01-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001210978	SCV002553316	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270154	SCV002553317	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
GeneDx	RCV001579834	SCV003805453	uncertain significance	not provided	2023-02-21	criteria provided, single submitter	clinical testing	Reported in a Dutch individual with an ascending aortic aneurysm and atrial fibrillation (Overwater et al., 2018), although family history and segregation details were not available; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29907982)
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579834	SCV001808670	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001579834	SCV001955364	uncertain significance	not provided		no assertion criteria provided	clinical testing