ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.487C>T (p.Arg163Trp)

gnomAD frequency: 0.00006  dbSNP: rs367707092
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000517091 SCV000614306 benign not specified 2021-02-26 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001171944 SCV001334854 uncertain significance not provided 2020-02-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001171944 SCV002188182 uncertain significance not provided 2023-12-09 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 163 of the NOTCH3 protein (p.Arg163Trp). This variant is present in population databases (rs367707092, gnomAD 0.02%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NOTCH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 447852). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NOTCH3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genetics and Molecular Pathology, SA Pathology RCV002272274 SCV002556508 uncertain significance Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 2020-06-12 criteria provided, single submitter clinical testing PM1, PP3
Ambry Genetics RCV002527502 SCV003699569 uncertain significance Inborn genetic diseases 2021-08-12 criteria provided, single submitter clinical testing The c.487C>T (p.R163W) alteration is located in exon 4 (coding exon 4) of the NOTCH3 gene. This alteration results from a C to T substitution at nucleotide position 487, causing the arginine (R) at amino acid position 163 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx RCV001171944 SCV005201386 uncertain significance not provided 2023-09-01 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV002272274 SCV005373865 uncertain significance Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 2024-09-22 criteria provided, single submitter clinical testing

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