Submissions for variant NM_000435.3(NOTCH3):c.1567G>A (p.Val523Met)

gnomAD frequency: 0.00005  dbSNP: rs564452430

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001127908	SCV001287266	benign	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Ambry Genetics	RCV003163286	SCV003878256	uncertain significance	Inborn genetic diseases	2023-01-31	criteria provided, single submitter	clinical testing	The c.1567G>A (p.V523M) alteration is located in exon 10 (coding exon 10) of the NOTCH3 gene. This alteration results from a G to A substitution at nucleotide position 1567, causing the valine (V) at amino acid position 523 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV003334034	SCV004042037	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	NOTCH3: BS2
Labcorp Genetics (formerly Invitae), Labcorp	RCV003334034	SCV004631862	benign	not provided	2023-10-13	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV003334034	SCV005408764	uncertain significance	not provided	2023-06-21	criteria provided, single submitter	clinical testing	BP1
PreventionGenetics, part of Exact Sciences	RCV004738165	SCV005351323	uncertain significance	NOTCH3-related disorder	2024-04-24	no assertion criteria provided	clinical testing	The NOTCH3 c.1567G>A variant is predicted to result in the amino acid substitution p.Val523Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.029% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.