ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.6409C>G (p.Leu2137Val)

dbSNP: rs2046639059
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001875349 SCV002148016 uncertain significance not provided 2022-07-12 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2137 of the NOTCH3 protein (p.Leu2137Val). This variant is not present in population databases (gnomAD no frequency). 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: 1386605). 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 not 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.
Ambry Genetics RCV004041399 SCV004990238 uncertain significance Inborn genetic diseases 2023-11-17 criteria provided, single submitter clinical testing The c.6409C>G (p.L2137V) alteration is located in exon 33 (coding exon 33) of the NOTCH3 gene. This alteration results from a C to G substitution at nucleotide position 6409, causing the leucine (L) at amino acid position 2137 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Athena Diagnostics RCV001875349 SCV005621199 uncertain significance not provided 2023-10-02 criteria provided, single submitter clinical testing Available data are insufficient to determine the clinical significance of the variant at this time. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) Computational tools disagree on the variant's effect on normal protein function. Greater than 90% of NOTCH3 pathogenic variants associated with CADASIL involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain (PMID: 32457593, 20301673).

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