Submissions for variant NM_017617.5(NOTCH1):c.4571C>T (p.Ala1524Val)

gnomAD frequency: 0.00001  dbSNP: rs774374213

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000524021	SCV000620389	uncertain significance	not provided	2017-08-24	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the NOTCH1 gene. The A1524V variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). However, the A1524V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function.
Invitae	RCV001312893	SCV001503364	benign	Adams-Oliver syndrome 5	2023-08-17	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001312893	SCV002553408	uncertain significance	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270630	SCV002553409	uncertain significance	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000524021	SCV004162017	uncertain significance	not provided	2022-12-01	criteria provided, single submitter	clinical testing	NOTCH1: PP2, BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479150	SCV004222699	likely benign	not specified	2023-11-15	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.4571C>T (p.Ala1524Val) results in a non-conservative amino acid change located in the Notch domain (IPR000800) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.5e-05 in 1581660 control chromosomes (gnomAD v4.0.0). The observed variant frequency is approximately 23 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.4571C>T in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have reported this variant to ClinVar after 2014 with conflicting assessments (benign, n = 1; VUS, n = 2). Based on the evidence outlined above, the variant was classified as likely benign.