ClinVar Miner

Submissions for variant NM_024408.4(NOTCH2):c.3995G>A (p.Arg1332His)

gnomAD frequency: 0.00010  dbSNP: rs587609362
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001854666 SCV002137901 uncertain significance Hajdu-Cheney syndrome 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1332 of the NOTCH2 protein (p.Arg1332His). This variant is present in population databases (rs587609362, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of Alagille syndrome (PMID: 28776642). ClinVar contains an entry for this variant (Variation ID: 134973). 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 95%. 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 RCV002498575 SCV002783560 uncertain significance Alagille syndrome due to a NOTCH2 point mutation; Hajdu-Cheney syndrome 2022-04-14 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003398734 SCV004104681 uncertain significance NOTCH2-related condition 2023-10-04 criteria provided, single submitter clinical testing The NOTCH2 c.3995G>A variant is predicted to result in the amino acid substitution p.Arg1332His. This variant has been reported in the heterozygous state in an infant with neonatal cholestasis, but no other features of Allagille syndrome (Stalke et al. 2018. PubMed ID: 28776642). This variant is reported in 0.030% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-120469132-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
ITMI RCV000121723 SCV000085921 not provided not specified 2013-09-19 no assertion provided reference population

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