Submissions for variant NM_017617.5(NOTCH1):c.3011C>T (p.Ser1004Leu)

gnomAD frequency: 0.00016  dbSNP: rs201163739

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000680592	SCV000808017	likely benign	Connective tissue disorder	2018-06-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000868987	SCV001010374	likely benign	Adams-Oliver syndrome 5	2024-01-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170153	SCV001332703	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-04-25	criteria provided, single submitter	clinical testing
GeneDx	RCV001568838	SCV001792779	uncertain significance	not provided	2024-05-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been published in association with cardiovascular disease to our knowledge; This variant is associated with the following publications: (PMID: 27870570)
Ambry Genetics	RCV001170153	SCV002753335	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-07-11	criteria provided, single submitter	clinical testing	The p.S1004L variant (also known as c.3011C>T), located in coding exon 19 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 3011. The serine at codon 1004 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is not well 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330897	SCV004039482	likely benign	not specified	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.3011C>T (p.Ser1004Leu) results in a non-conservative amino acid change located in the EGF-like domain (IPR008297) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 173498 control chromosomes. The observed variant frequency is approximately 280 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 phenotype (6.3e-07), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3011C>T in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=3) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV001568838	SCV004225188	uncertain significance	not provided	2022-11-23	criteria provided, single submitter	clinical testing	PP2
PreventionGenetics, part of Exact Sciences	RCV004544939	SCV004790124	likely benign	NOTCH1-related disorder	2022-07-28	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).