ClinVar Miner

Submissions for variant NM_024408.4(NOTCH2):c.4922A>C (p.Lys1641Thr)

gnomAD frequency: 0.00007  dbSNP: rs148354054
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001931607 SCV002199829 uncertain significance Hajdu-Cheney syndrome 2024-01-14 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 1641 of the NOTCH2 protein (p.Lys1641Thr). This variant is present in population databases (rs148354054, gnomAD 0.01%). 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: 1430909). 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 with a negative predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics RCV002503653 SCV002780726 uncertain significance Alagille syndrome due to a NOTCH2 point mutation; Hajdu-Cheney syndrome 2022-04-07 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003958427 SCV004768909 uncertain significance NOTCH2-related disorder 2024-01-31 criteria provided, single submitter clinical testing The NOTCH2 c.4922A>C variant is predicted to result in the amino acid substitution p.Lys1641Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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