Submissions for variant NM_000214.3(JAG1):c.267G>A (p.Gly89=)

gnomAD frequency: 0.08298  dbSNP: rs1051415

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035331	SCV000058979	benign	not specified	2016-12-13	criteria provided, single submitter	clinical testing	p.Gly89Gly in exon 2 of JAG1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 12% (1394/11536) of Latino chromosomes, including 83 homozygotes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1051415).
PreventionGenetics, part of Exact Sciences	RCV000035331	SCV000303018	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000343444	SCV000432957	benign	Isolated Nonsyndromic Congenital Heart Disease	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Ambry Genetics	RCV000620175	SCV000735009	benign	Cardiovascular phenotype	2015-06-12	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV001521586	SCV001730951	benign	Alagille syndrome due to a JAG1 point mutation	2024-02-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490472	SCV002799952	benign	Alagille syndrome due to a JAG1 point mutation; Tetralogy of Fallot; Deafness, congenital heart defects, and posterior embryotoxon; Charcot-Marie-Tooth disease, axonal, Type 2HH	2021-09-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035331	SCV004039516	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing	Variant summary: JAG1 c.267G>A alters a non-conserved nucleotide resulting in a synonymous change. Computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.095 in 281760 control chromosomes in the gnomAD database, including 1553 homozygotes. The observed variant frequency is approximately 4600 fold of the estimated maximal expected allele frequency for a pathogenic variant in JAG1 causing Alagille Syndrome 1 (2.1e-05), strongly suggesting that the variant is benign. Five ClinVar submitters have assessed the variant since 2014, and all submitters classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Clinical Genetics, Academic Medical Center	RCV000035331	SCV001924069	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723603	SCV001955039	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000035331	SCV001964210	benign	not specified		no assertion criteria provided	clinical testing