Submissions for variant NM_017617.5(NOTCH1):c.2576C>T (p.Thr859Met)

gnomAD frequency: 0.00004  dbSNP: rs199505287

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002315141	SCV000739513	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-12	criteria provided, single submitter	clinical testing	The p.T859M variant (also known as c.2576C>T), located in coding exon 16 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 2576. The threonine at codon 859 is replaced by methionine, an amino acid with similar properties. This amino acid position is poorly 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 alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000655238	SCV000777168	benign	Adams-Oliver syndrome 5	2024-12-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001558346	SCV001780272	uncertain significance	not provided	2023-05-04	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 does not alter protein structure/function
Genome-Nilou Lab	RCV000655238	SCV002553543	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270922	SCV002553544	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483735	SCV002788309	uncertain significance	Aortic valve disease 1; Adams-Oliver syndrome 5	2021-10-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056344	SCV005726788	likely benign	not specified	2024-11-11	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.2576C>T (p.Thr859Met) results in a non-conservative amino acid change located in the Growth factor receptor domain (IPR009030) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 1612768 control chromosomes. The observed variant frequency is approximately 57.54 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.2576C>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: 520097). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004544814	SCV004790710	uncertain significance	NOTCH1-related disorder	2023-11-30	no assertion criteria provided	clinical testing	The NOTCH1 c.2576C>T variant is predicted to result in the amino acid substitution p.Thr859Met. To our knowledge, this variant has not been reported in the literature in individuals with NOTCH1-related disorders. This variant is reported in 0.0063% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.