ClinVar Miner

Submissions for variant NM_024408.4(NOTCH2):c.6103A>C (p.Asn2035His)

gnomAD frequency: 0.00001  dbSNP: rs745697811
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000591699 SCV000705979 uncertain significance not provided 2017-01-27 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005027708 SCV005650542 uncertain significance Alagille syndrome due to a NOTCH2 point mutation; Hajdu-Cheney syndrome 2023-12-24 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV005091568 SCV005846742 uncertain significance Hajdu-Cheney syndrome 2024-05-23 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 2035 of the NOTCH2 protein (p.Asn2035His). This variant is present in population databases (rs745697811, 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: 500159). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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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