ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.3427C>T (p.Arg1143Cys)

gnomAD frequency: 0.00003  dbSNP: rs60373464
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000991705 SCV001143378 pathogenic not provided 2022-03-29 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Pathogenic variants in the EGF-like repeat domains 7-34 have a higher population frequency than variants in the EGF-like repeat domains 1-6. Therefore, variants in domains 7-34 may be associated with milder disease or may possibly be non-penetrant (PMID: 27844030, 30032161). This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Greater than 90% of pathogenic variants identified in NOTCH3 involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain.
Labcorp Genetics (formerly Invitae), Labcorp RCV000991705 SCV003275528 uncertain significance not provided 2022-05-07 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 1143 of the NOTCH3 protein (p.Arg1143Cys). This variant is present in population databases (rs60373464, gnomAD 0.005%). This missense change has been observed in individual(s) with NOTCH3-related conditions (PMID: 28991717, 32277177). ClinVar contains an entry for this variant (Variation ID: 804632). 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. 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.
Baylor Genetics RCV003333115 SCV004040982 likely pathogenic Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 2023-02-06 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000991705 SCV004224580 uncertain significance not provided 2022-09-30 criteria provided, single submitter clinical testing PM1

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