ClinVar Miner

Submissions for variant NM_000214.3(JAG1):c.2118_2121CAGT[1] (p.Gln708fs) (rs727504412)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844632 SCV000204275 pathogenic Arteriohepatic dysplasia; Heart, malformation of 2011-03-09 criteria provided, single submitter clinical testing The Gln708fs variant is predicted to cause a frameshift, which alters the protei n's amino acid sequence beginning at codon 708 and leads to a premature stop cod on 34 amino acids downstream. This alteration is then predicted to lead to a tru ncated or absent protein (loss of function). This variant has been reported in o ne child with Alagille syndrome as well as the mildly affected mother. Absence from 100 healthy control chromosomes supports a pathogenic role (Li 1997, varian t reported as 2531del4). In addition, it was reported as de novo in 5 additional , unrelated individuals with Alagille syndrome (Crosnier 1999 - variant reported as 2535-2538delCAGT). Loss of function is an established mechanism of disease f or the JAG1 gene and is typically associated with Alagille syndrome (GeneReviews ). In summary, the Gln708fs variant meets our criteria for pathogenicity (http:/ / and is highly likely to be causative for disease.
GeneDx RCV000199484 SCV000250486 pathogenic not provided 2016-06-27 criteria provided, single submitter clinical testing The c.2122_2125delCAGT pathogenic variant in the JAG1 gene has been reported previously in association with Alagille syndrome (Li et al., 1997; Jurkiewicz et al., 2005). The deletion causes a frameshift starting with codon Glutamine 708, changes this amino acid to a Valine residue and creates a premature Stop codon at position 34 of the new reading frame, denoted p.Gln708ValfsX34. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Invitae RCV000154602 SCV000545815 pathogenic Alagille syndrome 1 2018-06-26 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotides from exon 17 of the JAG1 mRNA (c.2122_2125delCAGT), causing a frameshift at codon 708. This creates a premature translational stop signal (p.Gln708Valfs*34) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in JAG1 are known to be pathogenic. This particular variant has been reported in the literature in individuals with Alagille syndrome  (PMID: 9207788, 15712272, 25676721, 22488849, 12442286). This variant is also known as c.2531_2534delCAGT in the literature. ClinVar contains an entry for this variant (Variation ID: 177941). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000199484 SCV000707420 pathogenic not provided 2017-04-05 criteria provided, single submitter clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes RCV000199484 SCV000778280 pathogenic not provided 2017-08-17 no assertion criteria provided clinical testing

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