ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.2149C>T (p.Arg717Cys)

gnomAD frequency: 0.00004  dbSNP: rs144163298
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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 RCV000991701 SCV001143369 uncertain significance not provided 2022-04-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV001266935 SCV001445116 uncertain significance Inborn genetic diseases 2018-06-19 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000991701 SCV001501696 likely pathogenic not provided 2020-10-01 criteria provided, single submitter clinical testing
Invitae RCV000991701 SCV001563444 pathogenic not provided 2023-10-13 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 717 of the NOTCH3 protein (p.Arg717Cys). This variant is present in population databases (rs144163298, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of NOTCH3-related conditions (PMID: 26308724, 33268848, 33310205, 34841502, 35822697; Invitae). ClinVar contains an entry for this variant (Variation ID: 804628). 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. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002471003 SCV002768626 likely pathogenic Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 2022-02-02 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely Pathogenic. Following criteria are met: 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine (exon 14). (N) 0251 - Variant is heterozygous. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (10 heterozygous, 0 homozygous). (P) 0309 - Two alternative amino acid changes at the same position have been observed in gnomAD (histidine and glycine: 3 heterozygotes each, 0 homozygotes). (N) 0803 - Low previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least one patient with CADASIL (PMID: 26308724). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1005 - Clinically accredited laboratory assay specific to gene product shows abnormal protein function. Granular rounded osmiophilic deposits, indicative of CADASIL, have been found in skin biopsy of this patient (Alfred Health pathology report). (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0600 - Variant is located in an annotated domain or motif. This variant is located within the 18 th repeat of the EGFr domain (PMID:27844030). Variants involving cysteines in the EGFr domains 1 to 6 are responsible for the classic CADASIL phenotype, whereas those in EGFr 7 to 34 domains are associated to a milder and later onset which may even be non-penetrant (PMID: 30032161). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0103 - Both loss- (missense) and gain-of-function (truncating in the last exon) are known mechanisms of disease for this gene, and have been associated with CADASIL (PMID:14714274; PMID:25914166). (N) 1101 - Very strong and specific phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Myllykangas group, University of Helsinki RCV001263185 SCV001250697 uncertain significance Vascular dementia 2020-04-01 no assertion criteria provided research

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