ClinVar Miner

Submissions for variant NM_000214.3(JAG1):c.821G>A (p.Gly274Asp) (rs28939668)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000555146 SCV000645537 likely pathogenic Alagille syndrome 1 2017-05-11 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 274 of the JAG1 protein (p.Gly274Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with tetralogy of Fallot in a large family (PMID:11152664).  ClinVar contains an entry for this variant (Variation ID: 7624). Experimental studies have shown that this missense change has a deleterious effect on several aspects of JAG1 protein function including structural stability, localization and ability to activate NOTCH signaling  (PMID: 19780835, 12649809). In summary this is a rare missense change which has been shown to segregate with disease in one family and affects protein function, for these reasons it has been classified as Likely Pathogenic.
OMIM RCV000008063 SCV000028268 pathogenic Tetralogy of Fallot 2003-04-01 no assertion criteria provided literature only

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