ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.397C>T (p.Arg133Cys) (rs137852642)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415016 SCV000493059 likely pathogenic Recurrent subcortical infarcts 2013-11-28 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000516340 SCV000614294 pathogenic not provided 2017-10-17 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002270 SCV001160148 pathogenic not specified 2018-12-03 criteria provided, single submitter clinical testing The NOTCH3 c.397C>T; p.Arg133Cys variant (rs137852642) has been described in multiple individuals affected with CADASIL (Joutel 1997, Maclean 2005, Mykkanen 2004). This variant is reported as pathogenic or likely pathogenic in ClinVar (Variation ID: 9225), 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 133 is moderately conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. In vitro characterization of this variant protein demonstrates increased spontaneous multimerization compared to wild-type (Opherk 2009). Based on available information, this variant is considered to be pathogenic. References: Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. Maclean A et al. Spontaneous lobar haemorrhage in CADASIL. J Neurol Neurosurg Psychiatry. 2005 Mar;76(3):456-7. Mykkanen K et al. Detection of the founder effect in Finnish CADASIL families. Eur J Hum Genet. 2004 Oct;12(10):813-9. Opherk C et al. CADASIL mutations enhance spontaneous multimerization of NOTCH3. Hum Mol Genet. 2009 Aug 1;18(15):2761-7.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001199011 SCV001370006 pathogenic Visual impairment; Leukoencephalopathy; Hearing abnormality; Paresthesia 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PP3. This variant was detected in heterozygous state.
OMIM RCV000009806 SCV000030027 pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 2009-08-01 no assertion criteria provided literature only
GeneReviews RCV000009806 SCV000987225 pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 2019-02-19 no assertion criteria provided literature only
GenomeConnect - CureCADASIL RCV000009806 SCV001156351 not provided Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 no assertion provided phenotyping only Variant interpreted as Pathogenic and most recently reported on 09-17-2018 by Lab or GTR ID 1012. Variant also interpreted as Pathogenic and reported on 05-12-2019 by GTR ID 500035. 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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