ClinVar Miner

Submissions for variant NM_024408.4(NOTCH2):c.3298G>A (p.Val1100Met)

gnomAD frequency: 0.00002  dbSNP: rs782536553
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002004633 SCV002230391 uncertain significance Hajdu-Cheney syndrome 2023-12-11 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1100 of the NOTCH2 protein (p.Val1100Met). This variant is present in population databases (rs782536553, gnomAD 0.004%). 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: 1449537). 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 RCV002484781 SCV002780195 uncertain significance Alagille syndrome due to a NOTCH2 point mutation; Hajdu-Cheney syndrome 2022-02-02 criteria provided, single submitter clinical testing

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