ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.328C>T (p.Arg110Cys) (rs775836288)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000516674 SCV000614280 pathogenic not provided 2019-01-11 criteria provided, single submitter clinical testing The variant disrupts a cysteine residue in an EGF-like repeat domain, which are important for the structure of this protein. Therefore it is expected to severely affect the function of the protein. Found in at least one symptomatic patient, and not found in general population data. Predicted to have a damaging effect on the protein. Co-occurs with otherwise positive results less than expected. Inconclusive segregation with disease.
Mendelics RCV000990179 SCV001141029 pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002189 SCV001160060 pathogenic not specified 2018-10-25 criteria provided, single submitter clinical testing The NOTCH3 c.328C>T; p.Arg110Cys variant is reported in the literature in multiple individuals and families affected with CADASIL (Dichgans 2000, Hung 2018, Joutel 1997, Khan 2016, Opherk 2004, Peters 2005, Singhal 2004, Uyguner 2006, Wang 2011). This variant is reported in ClinVar (Variation ID: 447831), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 110 is highly conserved, but computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. However, this variant lies with an EGF-like repeat domain, and pathogenic variants resulting in the gain or loss of a cysteine residue are common in these repeats and are predicted to disrupt protein structure (Dichgans 2000, Joutel 2007). Based on available information, the p.Arg110Cys variant is considered to be likely pathogenic. References: Dichgans M et al. Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains. Eur J Hum Genet. 2000 Apr;8(4):280-5. Hung LY et al. Genetic diagnosis of CADASIL in three Hong Kong Chinese patients: A novel mutation within the intracellular domain of NOTCH3. J Clin Neurosci. 2018 Oct;56:95-100. Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. Khan MT et al. Successful Use of Intravenous Tissue Plasminogen Activator as Treatment for a Patient with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy: A Case Report and Review of Literature. J Stroke Cerebrovasc Dis. 2016 Apr;25(4):e53-7. 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. Peters N et al. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol. 2005 Jul;62(7):1091-4. Singhal S et al. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain. 2004 Sep;127(Pt 9):2031-8. Uyguner ZO et al. The R110C mutation in Notch3 causes variable clinical features in two Turkish families with CADASIL syndrome. J Neurol Sci. 2006 Jul 15;246(1-2):123-30. Wang Z et al. NOTCH3 mutations and clinical features in 33 mainland Chinese families with CADASIL. J Neurol Neurosurg Psychiatry. 2011 May;82(5):534-9.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000516674 SCV001246159 pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197179 SCV001367815 uncertain significance Respiratory disease 2019-01-09 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PP3,PP4. This variant was detected in heterozygous state.
GenomeConnect - CureCADASIL RCV000990179 SCV001156354 not provided Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 02-13-2015 by Lab or GTR ID 303161. 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.

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