Submissions for variant NM_000214.3(JAG1):c.95C>A (p.Ser32Ter)

dbSNP: rs2122644940

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001908477	SCV002162198	pathogenic	Alagille syndrome due to a JAG1 point mutation	2021-09-06	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with JAG1-related conditions. This sequence change creates a premature translational stop signal (p.Ser32*) 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 (ExAC no frequency).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001908477	SCV002767022	pathogenic	Alagille syndrome due to a JAG1 point mutation	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Alagille syndrome 1 (MIM#118450) and tetralogy of Fallot (MIM#187500). The mechanism for Charcot-Marie-Tooth disease, axonal, type 2HH (MIM#619574) is not clearly established, but loss of function is suggested (PMID: 32065591). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is located within the first 102 nucleotides of the coding sequence and is predicted to escape nonsense-mediated decay. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0703 - Other NMD-escape variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. These variants have been reported as likely pathogenic and pathogenic, and observed in several individuals with Alagille syndrome (ClinVar, PMID: 10220506, PMID: 11139247). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been previously described as pathogenic, and observed in an individual with pulmonary valve stenosis and dysmorphic facial features in the newborn period (ClinVar, personal communication). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by segregation analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign