Submissions for variant NM_017617.5(NOTCH1):c.6509G>A (p.Ser2170Asn)

gnomAD frequency: 0.00014  dbSNP: rs200254239

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000526597	SCV000659481	likely benign	Adams-Oliver syndrome 5	2024-01-25	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769586	SCV000900983	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2021-01-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001544564	SCV001763719	uncertain significance	not provided	2021-04-29	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 477961; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function
Ambry Genetics	RCV000769586	SCV002655574	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-19	criteria provided, single submitter	clinical testing	The p.S2170N variant (also known as c.6509G>A), located in coding exon 34 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 6509. The serine at codon 2170 is replaced by asparagine, 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	RCV003403345	SCV004122769	likely benign	not specified	2023-10-11	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.6509G>A (p.Ser2170Asn) results in a conservative amino acid change in 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 0.00014 in 247136 control chromosomes. The observed variant frequency is approximately 220.12 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.6509G>A in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001544564	SCV004563891	likely benign	not provided	2023-02-17	criteria provided, single submitter	clinical testing