Submissions for variant NM_000214.3(JAG1):c.439+1G>A

dbSNP: rs863223648

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199991	SCV000250455	pathogenic	not provided	2015-05-12	criteria provided, single submitter	clinical testing	The c.439+1 G>A splice site mutation in the JAG1 gene has been previously reported in association with Alagille syndrome (Crosnier et al., 2001; Jurkiewicz et al. 2014). This mutation destroys the canonical splice donor site in intron 3, and is expected to cause abnormal gene splicing.This mutation destroys the canonical splice donor site in intron 3, and is expected to cause abnormal gene splicing. This variant was found in JAG1-T1
Eurofins Ntd Llc (ga)	RCV000199991	SCV000707317	pathogenic	not provided	2017-03-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853157	SCV002242883	pathogenic	Alagille syndrome due to a JAG1 point mutation	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the JAG1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in JAG1 are known to be pathogenic (PMID: 11180599). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Alagille syndrome (PMID: 11139247, 11180599, 29483232, 31343788). ClinVar contains an entry for this variant (Variation ID: 213529). 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.
Genomic Medicine Lab, University of California San Francisco	RCV001853157	SCV004847132	pathogenic	Alagille syndrome due to a JAG1 point mutation	2023-02-23	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001853157	SCV005068255	pathogenic	Alagille syndrome due to a JAG1 point mutation	2024-07-01	criteria provided, single submitter	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV000845195	SCV000987131	likely pathogenic	Atypical coarctation of aorta	2018-02-26	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004553065	SCV004117208	pathogenic	JAG1-related disorder	2024-02-09	no assertion criteria provided	clinical testing	The JAG1 c.439+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in multiple individuals with Alagille syndrome (Table 1, Crosnier et al. 2000. PubMed ID: 11139247; Table 1, Jurkiewicz et al. 2014. PubMed ID: 24748328; Ohashi et al. 2017. PubMed ID: 28695677), as well as an individual with midaortic syndrome (Table 1, Warejko et al. 2018. PubMed ID: 29483232). This variant has not been reported in a large population database, indicating this variant is rare. Variants that disrupt the consensus splice donor site in JAG1 are expected to be pathogenic. This variant is interpreted as pathogenic.