chr19-15192134-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000435.3(NOTCH3):c.505C>T(p.Arg169Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169H) has been classified as Likely benign.
Frequency
Consequence
NM_000435.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH3 | NM_000435.3 | c.505C>T | p.Arg169Cys | missense_variant | 4/33 | ENST00000263388.7 | |
NOTCH3 | XM_005259924.5 | c.505C>T | p.Arg169Cys | missense_variant | 4/32 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH3 | ENST00000263388.7 | c.505C>T | p.Arg169Cys | missense_variant | 4/33 | 1 | NM_000435.3 | P1 | |
NOTCH3 | ENST00000601011.1 | c.502C>T | p.Arg168Cys | missense_variant | 4/23 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460660Hom.: 0 Cov.: 40 AF XY: 0.00000275 AC XY: 2AN XY: 726678
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 10, 2023 | PP1, PP2, PP4, PM1, PM2, PS3, PS4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Sep 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 169 of the NOTCH3 protein (p.Arg169Cys). 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 (PMID: 12754354, 25412914, 28334938). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9219). 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) performed at Invitae indicates that this missense variant is expected to disrupt NOTCH3 protein function. Experimental studies have shown that this missense change affects NOTCH3 function (PMID: 21940951). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 25, 2020 | Reported in individuals with CADASIL in published literature, including one family with an atypical presentation with symptoms of autoimmunity (Joutel et al., 1996; Joutel et al., 1997; Paraskevas et al., 2014); Published studies demonstrate that knock out mice with the R170C variant, which corresponds to R169C in humans, develop features of CADASIL (Wallays et al., 2011; Cognat et al., 2014; Joutel et al., 2010); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32277177, 32581362, 31753008, 32344328, 31418856, 30014602, 25412914, 20071773, 11909813, 28334938, 9388399, 12754354, 15287509, 8878478, 24425116, 21940951, 32765252) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | NOTCH3: PM1:Strong, PM2, PS4:Moderate, PP2, PP4, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 30, 2023 | The NOTCH3 c.505C>T; p.Arg169Cys variant (rs28933696) is reported in the medical literature in individuals with CADASIL (Lynch 2017, Opherk 2004, Paraskevas 2014). Additionally, a mouse model with this variant shows hallmarks of disease (Cognat 2014). The variant is described in the ClinVar database (Variation ID: 9219) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.726). Considering available information, this variant is classified as pathogenic. References: Cognat E et al. Archetypal Arg169Cys mutation in NOTCH3 does not drive the pathogenesis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy via a loss-of-function mechanism. Stroke. 2014 Mar;45(3):842-9. PMID: 24425116. Lynch DS et al. Clinical and genetic characterization of leukoencephalopathies in adults. Brain. 2017 May 1;140(5):1204-1211. PMID: 28334938. Opherk C et al. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain. 2004 Nov;127(Pt 11):2533-9. PMID: 15364702. Paraskevas GP et al. CADASIL and autoimmunity: coexistence in a family with the R169C mutation at exon 4 of the NOTCH3 gene. Cerebrovasc Dis. 2014;38(4):302-7. PMID: 25412914 - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 15, 2022 | This variant has been identified in multiple unrelated individuals with 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 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). - |
Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 16, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 24425116) - The c.505C>T;p.(Arg169Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 9219; PMID: 28334938; PMID: 25412914) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (EGF_CA; hEGF) - PM1. This variant is not present in population databases (rs28933696- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant co-segregated with disease in multiple affected family members (PMID: 25412914) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 22, 1997 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect - CureCADASIL | - | Variant interpreted as Pathogenic and reported on 07-16-2019 by lab or GTR ID University of Washington Laboratory for Precision Diagnostics. 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 07, 2022 | - - |
NOTCH3-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 13, 2023 | The NOTCH3 c.505C>T variant is predicted to result in the amino acid substitution p.Arg169Cys. This variant has been observed in numerous patients with CADASIL and is located in a mutation hotspot (Ni et al. 2022. PubMed ID: 35822697). Its pathogenicity is supported by functional studies (Lynch et al. 2017. PubMed ID: 28334938; Wallays et al. 2011. PubMed ID: 21940951). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Most CADASIL causing variants in the NOTCH3 gene result in the gain or loss of one or more cysteine residues in the extracellular domain of the protein, as seen in this patient. This patient’s variant adds a cysteine residue and is located in the extracellular EGF-like domain 4. Pathogenic variants in EGF-like domains 1-6 appear to be fully penetrant and are usually associated with the classical CADASIL phenotype. However, there is variability in disease severity (OMIM #125310; Rutten et al. 2016. PubMed ID: 27844030; Rutten et al. 2019. PubMed ID: 30032161). This variant is interpreted as pathogenic. - |
Lateral meningocele syndrome;C3809084:Myofibromatosis, infantile, 2;C4551768:Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 28, 2021 | - - |
Stroke disorder;C0338480:Migraine without aura Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at