ClinVar Miner

Submissions for variant NM_000214.3(JAG1):c.1223C>T (p.Thr408Met)

gnomAD frequency: 0.00001  dbSNP: rs773039210
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001227723 SCV001400093 uncertain significance Alagille syndrome due to a JAG1 point mutation 2024-11-13 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 408 of the JAG1 protein (p.Thr408Met). This variant is present in population databases (rs773039210, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with JAG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 955136). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on JAG1 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.
MGZ Medical Genetics Center RCV001227723 SCV002580318 uncertain significance Alagille syndrome due to a JAG1 point mutation 2021-08-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV004032610 SCV005032977 uncertain significance Cardiovascular phenotype 2023-12-08 criteria provided, single submitter clinical testing The p.T408M variant (also known as c.1223C>T), located in coding exon 9 of the JAG1 gene, results from a C to T substitution at nucleotide position 1223. The threonine at codon 408 is replaced by methionine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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