ClinVar Miner

Submissions for variant NM_024408.4(NOTCH2):c.4142G>A (p.Ser1381Asn)

gnomAD frequency: 0.00004  dbSNP: rs886044453
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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) RCV000354092 SCV000344998 uncertain significance not provided 2016-08-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV002519341 SCV003579408 uncertain significance Inborn genetic diseases 2021-10-12 criteria provided, single submitter clinical testing The c.4142G>A (p.S1381N) alteration is located in exon 25 (coding exon 25) of the NOTCH2 gene. This alteration results from a G to A substitution at nucleotide position 4142, causing the serine (S) at amino acid position 1381 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Invitae RCV003633497 SCV004551102 uncertain significance Hajdu-Cheney syndrome 2024-01-25 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1381 of the NOTCH2 protein (p.Ser1381Asn). This variant is present in population databases (no rsID available, 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: 290439). 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.

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