Submissions for variant NM_000435.3(NOTCH3):c.3062A>G (p.Tyr1021Cys)

gnomAD frequency: 0.00001  dbSNP: rs1167405466

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000518485	SCV000614273	pathogenic	not provided	2023-02-02	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features of CADASIL. This variant occurs as the most likely explanation for disease in a significant number of cases, suggesting this variant is associated with disease. This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. 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).
GeneDx	RCV000518485	SCV000779642	likely pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	Reported previously in the heterozygous state in individuals with clinical features of CADASIL (PMID: 12146805, 18803652, 20038773, 32765252, 31998484, 34335700, 35775048; Ivan Tourtourikov et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37873835, 22878905, 15995828, 18803652, 20038773, 22367627, 21786151, 32765252, 32912545, 35754959, 34335700, 31998484, Ivan2021[Article], 37476306, Uemura_2022, 35775048, 30956055, 32277177, 12146805, 24844136)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000518485	SCV001474559	likely pathogenic	not provided	2023-11-24	criteria provided, single submitter	clinical testing	The NOTCH3 c.3062A>G; p.Tyr1021Cys variant (rs1167405466) is reported in the literature in several individuals affected with CADASIL (Hu 2021, Kalimo 2002, Mukai 2020, Pantoni 2010, Petrea 2019, Piccirillo 2008, Uppal 2019). This variant is also reported in ClinVar (Variation ID: 447825). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.658). However, this variant occurs in an EGF-like domain, and most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014). Based on available information, this variant is considered to be likely pathogenic. References: Hu Y et al. NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients. Front Genet. 2021 Jul 15;12:705284. PMID: 34335700. Kalimo H et al. CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. Brain Pathol. 2002 Jul;12(3):371-84. PMID: 12146805. Mukai M et al. Genotype-phenotype correlations and effect of mutation location in Japanese CADASIL patients. J Hum Genet. 2020 Aug;65(8):637-646. PMID: 32277177. Pantoni L et al. Comparison of clinical, familial, and MRI features of CADASIL and NOTCH3-negative patients. Neurology. 2010 Jan 5;74(1):57-63. PMID: 20038773. Petrea RE et al. Novel Neuroimaging "Encephalitic-Like Brain MRI Phenotype" in a Patient with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Acta Sci Neurol. 2019 Dec 9;3(1):03-08. Piccirillo G et al. Increased QT variability in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Eur J Neurol. 2008 Nov;15(11):1216-21. PMID: 18803652. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. PMID: 24844136. Uppal M et al. CADASIL presenting as late-onset mania with anosognosia. Clin Case Rep. 2019 Dec 8;8(1):47-50. PMID: 31998484.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000518485	SCV001583422	pathogenic	not provided	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1021 of the NOTCH3 protein (p.Tyr1021Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (PMID: 18803652, 21786151, 31998484, 32277177). ClinVar contains an entry for this variant (Variation ID: 447825). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NOTCH3 protein function. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000518485	SCV003815120	likely pathogenic	not provided	2022-03-17	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000518485	SCV004225116	likely pathogenic	not provided	2023-04-18	criteria provided, single submitter	clinical testing	PP2, PP4, PM1, PS4
GenomeConnect - CureCADASIL	RCV001800727	SCV002047453	not provided	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1; Lateral meningocele syndrome; Myofibromatosis, infantile, 2		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 10-06-2017 by lab or GTR ID Fulgent. 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. Phenotypic details are available under supporting information.