ClinVar Miner

Submissions for variant NM_024408.4(NOTCH2):c.5177G>A (p.Arg1726His)

dbSNP: rs1557804884
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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) RCV000733343 SCV000861396 uncertain significance not provided 2018-05-22 criteria provided, single submitter clinical testing
Invitae RCV001868985 SCV002174932 uncertain significance Hajdu-Cheney syndrome 2022-07-26 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 1726 of the NOTCH2 protein (p.Arg1726His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with NOTCH2-related conditions (PMID: 32368696). ClinVar contains an entry for this variant (Variation ID: 597278). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
PreventionGenetics, part of Exact Sciences RCV003396310 SCV004105892 uncertain significance NOTCH2-related condition 2023-09-03 criteria provided, single submitter clinical testing The NOTCH2 c.5177G>A variant is predicted to result in the amino acid substitution p.Arg1726His. This variant was reported de novo in at least one individual with congenital heart defects (Patient #1-06209 in supplementary databases 1 and 2, Edwards et al. 2020. PubMed ID: 32368696; Table S2, Sevim Bayrak et al. 2020. PubMed ID: 31941532). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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