ClinVar Miner

Submissions for variant NM_024408.4(NOTCH2):c.3556T>A (p.Tyr1186Asn)

gnomAD frequency: 0.00003  dbSNP: rs377058108
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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) RCV000732629 SCV000860604 uncertain significance not provided 2018-03-30 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001254707 SCV001430776 uncertain significance VATER association 2020-05-28 criteria provided, single submitter research The heterozygous p.Tyr1186Asn variant in NOTCH2 was identified by our study in 1 individual with VACTERL/vater association as well as this individuals mother whose affection status was unknown and was reported in the literature (PMID: 30143558). This variant has been identified in 0.02% (6/35436) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Tyr1186Asn variant is uncertain. ACMG/AMP Criteria applied: none (Richards 2015).
Fulgent Genetics, Fulgent Genetics RCV002477716 SCV002786589 uncertain significance Alagille syndrome due to a NOTCH2 point mutation; Hajdu-Cheney syndrome 2022-03-07 criteria provided, single submitter clinical testing
Invitae RCV002535286 SCV003270495 uncertain significance Hajdu-Cheney syndrome 2022-07-19 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1186 of the NOTCH2 protein (p.Tyr1186Asn). This variant is present in population databases (rs377058108, gnomAD 0.02%). 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: 596711). 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. 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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