ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.472G>A (p.Asp158Asn)

gnomAD frequency: 0.00006  dbSNP: rs544773641
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000518641 SCV000614305 likely benign not specified 2017-04-17 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001253585 SCV001429377 uncertain significance Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 2024-02-27 criteria provided, single submitter clinical testing Criteria applied: PS4_SUP,PM2_SUP,PP2,PP3
Labcorp Genetics (formerly Invitae), Labcorp RCV002527501 SCV003461969 uncertain significance not provided 2022-02-07 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 158 of the NOTCH3 protein (p.Asp158Asn). This variant is present in population databases (rs544773641, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 30076350). ClinVar contains an entry for this variant (Variation ID: 447851). 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.

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