Submissions for variant NM_000214.3(JAG1):c.2230C>T (p.Arg744Ter)

dbSNP: rs863223655

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196949	SCV000250465	pathogenic	not provided	2021-10-29	criteria provided, single submitter	clinical testing	Reported previously in multiple additional individuals with Alagille syndrome (Onouchi et al., 1999; Colliton et al., 2001; Guegan et al., 2012; Rocha et al., 2012; Jurkiewicz et al., 2014); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11180599, 21752016, 22759690, 24748328, 25525159, 34185059, 34071626, 9585603, 10429362)
Eurofins Ntd Llc (ga)	RCV000196949	SCV000708023	pathogenic	not provided	2018-05-24	criteria provided, single submitter	clinical testing
Invitae	RCV001038520	SCV001201990	pathogenic	Alagille syndrome due to a JAG1 point mutation	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg744*) in the JAG1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in JAG1 are known to be pathogenic (PMID: 11180599). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Allagile syndrome (PMID: 17241866, 21752016, 24748328). ClinVar contains an entry for this variant (Variation ID: 213538). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000196949	SCV002525838	pathogenic	not provided	2021-12-02	criteria provided, single submitter	clinical testing	PM2, PM6, PS4_moderate, PVS1
3billion	RCV001038520	SCV002573087	pathogenic	Alagille syndrome due to a JAG1 point mutation	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000213538 / PMID: 9585603). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
PreventionGenetics, part of Exact Sciences	RCV003417709	SCV004107037	pathogenic	JAG1-related condition	2022-10-23	criteria provided, single submitter	clinical testing	The JAG1 c.2230C>T variant is predicted to result in premature protein termination (p.Arg744*). This variant has been reported to be causative for Alagille syndrome (described as R739X, Krantz et al. 1998. PubMed ID: 9585603; Guegan et al. 2011. PubMed ID: 21752016; Jurkiewicz et al. 2014. PubMed ID: 24748328). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. Nonsense variants in JAG1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Genomics And Bioinformatics Analysis Resource, Columbia University	RCV001038520	SCV004024130	pathogenic	Alagille syndrome due to a JAG1 point mutation		no assertion criteria provided	research