ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.1819C>T (p.Arg607Cys) (rs777751303)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000415985 SCV000493485 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000415985 SCV000614242 pathogenic not provided 2019-06-12 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 found in general population data that is consistent with pathogenicity.
Fulgent Genetics,Fulgent Genetics RCV000763036 SCV000893513 likely pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1; Lateral meningocele syndrome; Infantile myofibromatosis 2 2018-10-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287012 SCV001473650 likely pathogenic none provided 2019-10-15 criteria provided, single submitter clinical testing The NOTCH3 c.1819C>T; p.Arg607Cys variant (rs777751303), also known as 1897C>T; R607C, is reported in the literature in multiple individuals and families affected with CADASIL (Dotti 2005, Escary 2000, Singhal 2004, Watanabe 2012). This variant is reported in ClinVar (Variation ID: 374637), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 607 is highly conserved and occurs in an EGF-like domain, but computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. However, most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014), and thus the p.Arg607Cys variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be likely pathogenic. References: Dotti MT et al. The spectrum of Notch3 mutations in 28 Italian CADASIL families. J Neurol Neurosurg Psychiatry. 2005 May;76(5):736-8. Escary JL et al. Evaluation of DHPLC analysis in mutational scanning of Notch3, a gene with a high G-C content. Hum Mutat. 2000 Dec;16(6):518-26. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. Singhal S et al. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain. 2004 Sep;127(Pt 9):2031-8. Watanabe M et al. An unusual case of elderly-onset cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with multiple cerebrovascular risk factors. J Stroke Cerebrovasc Dis. 2012 Feb;21(2):143-5.

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