ClinVar Miner

Submissions for variant NM_024408.4(NOTCH2):c.3467A>G (p.Asn1156Ser)

gnomAD frequency: 0.00003  dbSNP: rs782760871
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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) RCV000730967 SCV000858737 uncertain significance not provided 2017-12-14 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002485887 SCV002776110 uncertain significance Alagille syndrome due to a NOTCH2 point mutation; Hajdu-Cheney syndrome 2021-12-08 criteria provided, single submitter clinical testing
Invitae RCV002535184 SCV003489145 uncertain significance Hajdu-Cheney syndrome 2024-01-02 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1156 of the NOTCH2 protein (p.Asn1156Ser). This variant is present in population databases (rs782760871, gnomAD 0.005%). 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: 595426). 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.
Ambry Genetics RCV003165971 SCV003914224 uncertain significance Inborn genetic diseases 2023-03-02 criteria provided, single submitter clinical testing The c.3467A>G (p.N1156S) alteration is located in exon 21 (coding exon 21) of the NOTCH2 gene. This alteration results from a A to G substitution at nucleotide position 3467, causing the asparagine (N) at amino acid position 1156 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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