Submissions for variant NM_000214.3(JAG1):c.3329A>C (p.Asn1110Thr)

gnomAD frequency: 0.00011  dbSNP: rs150811951

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726021	SCV000341283	uncertain significance	not provided	2018-03-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000276199	SCV000432887	benign	Isolated Nonsyndromic Congenital Heart Disease	2018-01-13	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.
GeneDx	RCV000726021	SCV000581745	uncertain significance	not provided	2017-05-03	criteria provided, single submitter	clinical testing	The N1110T variant in the JAG1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N1110T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Asparagine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on currently available evidence, we interpret N1110T as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001052188	SCV001216386	likely benign	Alagille syndrome due to a JAG1 point mutation	2024-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002321960	SCV002606253	uncertain significance	Cardiovascular phenotype	2016-11-25	criteria provided, single submitter	clinical testing	The p.N1110T variant (also known as c.3329A>C), located in coding exon 26 of the JAG1 gene, results from an A to C substitution at nucleotide position 3329. The asparagine at codon 1110 is replaced by threonine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs150811951. Based on data from ExAC, the C allele has an overall frequency of approximately 0.012% (13/106164) total alleles studied. The highest observed frequency was 0.033% (3/9062) of African alleles. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.