Submissions for variant NM_000435.3(NOTCH3):c.160C>T (p.Arg54Cys)

dbSNP: rs1555730189

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516423	SCV000614231	pathogenic	not provided	2022-04-28	criteria provided, single submitter	clinical testing	This variant has been identified in at least one individual with clinical features of CADASIL. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Greater than 90% of pathogenic variants identified in NOTCH3 involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253276	SCV001428913	likely pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2017-12-27	criteria provided, single submitter	clinical testing
3billion	RCV001253276	SCV002318670	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2022-03-22	criteria provided, single submitter	clinical testing	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000447791, PMID:11102981). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 26270344, 24139282, 32277177, 26002683, 11102981). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.803>=0.6). A missense variant is a common mechanism . It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796220	SCV005418275	likely pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1; Lateral meningocele syndrome; Myofibromatosis, infantile, 2		criteria provided, single submitter	clinical testing	PS4+PM2_Supporting+PP2+PP3+PP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV000516423	SCV005838821	pathogenic	not provided	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 54 of the NOTCH3 protein (p.Arg54Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 19006080, 19242647, 26270344, 32277177). ClinVar contains an entry for this variant (Variation ID: 447791). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NOTCH3 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Genomics England Pilot Project, Genomics England	RCV001253276	SCV001760443	likely pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1		no assertion criteria provided	clinical testing
GenomeConnect - CureCADASIL	RCV002508218	SCV002818099	not provided	Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 02-03-2017 by Lab or GTR ID 1012. GenomeConnect-CureCADASIL assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.