ClinVar Miner

Submissions for variant NM_024408.4(NOTCH2):c.4733G>A (p.Arg1578His)

gnomAD frequency: 0.00001  dbSNP: rs751299682
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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) RCV000735015 SCV000863202 uncertain significance not provided 2018-08-29 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002485947 SCV002778203 uncertain significance Alagille syndrome due to a NOTCH2 point mutation; Hajdu-Cheney syndrome 2022-03-05 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003420316 SCV004118664 uncertain significance NOTCH2-related disorder 2023-04-11 criteria provided, single submitter clinical testing The NOTCH2 c.4733G>A variant is predicted to result in the amino acid substitution p.Arg1578His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-120466386-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Invitae RCV003633541 SCV004552662 uncertain significance Hajdu-Cheney syndrome 2024-01-16 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 1578 of the NOTCH2 protein (p.Arg1578His). This variant is present in population databases (rs751299682, gnomAD 0.006%). 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: 598586). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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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