Submissions for variant NM_017617.5(NOTCH1):c.7138G>A (p.Val2380Met)

gnomAD frequency: 0.00001  dbSNP: rs769693988

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000591716	SCV000703605	uncertain significance	not provided	2016-12-08	criteria provided, single submitter	clinical testing
Invitae	RCV001240610	SCV001413575	benign	Adams-Oliver syndrome 5	2024-01-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000591716	SCV001875203	uncertain significance	not provided	2021-08-20	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 498543; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918)
Genome-Nilou Lab	RCV001240610	SCV002553255	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270716	SCV002553256	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002368007	SCV002662719	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-01-24	criteria provided, single submitter	clinical testing	The p.V2380M variant (also known as c.7138G>A), located in coding exon 34 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 7138. The valine at codon 2380 is replaced by methionine, an amino acid with highly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330813	SCV004038825	uncertain significance	not specified	2023-08-22	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.7138G>A (p.Val2380Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 247728 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7138G>A in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance and one as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.