Submissions for variant NM_000435.3(NOTCH3):c.6325C>T (p.Arg2109Trp)

gnomAD frequency: 0.00001  dbSNP: rs199995195

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001124532	SCV001283504	uncertain significance	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2018-01-13	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV004960475	SCV005455446	uncertain significance	Inborn genetic diseases	2024-10-24	criteria provided, single submitter	clinical testing	The c.6325C>T (p.R2109W) alteration is located in exon 33 (coding exon 33) of the NOTCH3 gene. This alteration results from a C to T substitution at nucleotide position 6325, causing the arginine (R) at amino acid position 2109 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Athena Diagnostics	RCV004998656	SCV005622156	uncertain significance	not provided	2024-01-15	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (http://gnomad.broadinstitute.org) Computational tools predict that this variant is not damaging. Greater than 90% of NOTCH3 pathogenic variants associated with CADASIL involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain (PMID: 32457593, 20301673).
PreventionGenetics, part of Exact Sciences	RCV004545074	SCV004763114	uncertain significance	NOTCH3-related disorder	2023-12-30	no assertion criteria provided	clinical testing	The NOTCH3 c.6325C>T variant is predicted to result in the amino acid substitution p.Arg2109Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.