Submissions for variant NM_017617.5(NOTCH1):c.6283C>T (p.Arg2095Cys)

gnomAD frequency: 0.00007  dbSNP: rs780873661

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494409	SCV000582898	uncertain significance	not provided	2023-09-15	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Invitae	RCV001301819	SCV001491000	benign	Adams-Oliver syndrome 5	2023-11-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001301819	SCV002553311	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270590	SCV002553312	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002356809	SCV002655926	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-01-01	criteria provided, single submitter	clinical testing	The p.R2095C variant (also known as c.6283C>T), located in coding exon 34 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 6283. The arginine at codon 2095 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993987	SCV004813139	uncertain significance	not specified	2024-02-05	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.6283C>T (p.Arg2095Cys) results in a non-conservative amino acid change located in the ankyrin repeat-containing domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.1e-05 in 1612310 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is approximately equal to the maximum estimated frequency for a pathogenic variant in NOTCH1 causing Aortic Valve Disease (3.1e-05 vs 3.1e-05), suggesting the variant could be a benign polymorphism. To our knowledge, no occurrence of c.6283C>T in individuals affected with Aortic Valve Disease or 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: 430166). Based on the evidence outlined above, the variant was classified as uncertain significance.