ClinVar Miner

Submissions for variant NM_024408.4(NOTCH2):c.6338C>T (p.Pro2113Leu)

gnomAD frequency: 0.00005  dbSNP: rs767621140
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000594058 SCV000707829 uncertain significance not provided 2017-04-13 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002476330 SCV002798331 uncertain significance Alagille syndrome due to a NOTCH2 point mutation; Hajdu-Cheney syndrome 2022-01-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV002532593 SCV003683623 uncertain significance Inborn genetic diseases 2021-12-07 criteria provided, single submitter clinical testing The c.6338C>T (p.P2113L) alteration is located in exon 34 (coding exon 34) of the NOTCH2 gene. This alteration results from a C to T substitution at nucleotide position 6338, causing the proline (P) at amino acid position 2113 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Invitae RCV003522990 SCV004308418 uncertain significance Hajdu-Cheney syndrome 2023-07-06 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2113 of the NOTCH2 protein (p.Pro2113Leu). This variant is present in population databases (rs767621140, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with NOTCH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 501463). 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 NOTCH2 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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