ClinVar Miner

Submissions for variant NM_024408.4(NOTCH2):c.760G>T (p.Gly254Trp)

gnomAD frequency: 0.00001  dbSNP: rs1553202314
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000728755 SCV000856368 uncertain significance not provided 2017-08-24 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002477686 SCV002778030 uncertain significance Alagille syndrome due to a NOTCH2 point mutation; Hajdu-Cheney syndrome 2021-09-27 criteria provided, single submitter clinical testing
Invitae RCV002535091 SCV003289712 uncertain significance Hajdu-Cheney syndrome 2023-01-28 criteria provided, single submitter clinical testing 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. 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 expected to disrupt NOTCH2 protein function. ClinVar contains an entry for this variant (Variation ID: 593653). This variant has not been reported in the literature in individuals affected with NOTCH2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 254 of the NOTCH2 protein (p.Gly254Trp).
GeneDx RCV000728755 SCV003927667 uncertain significance not provided 2022-11-25 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV004026953 SCV004990213 uncertain significance Inborn genetic diseases 2023-10-27 criteria provided, single submitter clinical testing The c.760G>T (p.G254W) alteration is located in exon 5 (coding exon 5) of the NOTCH2 gene. This alteration results from a G to T substitution at nucleotide position 760, causing the glycine (G) at amino acid position 254 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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