ClinVar Miner

Submissions for variant NM_000214.3(JAG1):c.5G>T (p.Arg2Leu)

gnomAD frequency: 0.00006  dbSNP: rs1026004197
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000729658 SCV000857334 uncertain significance not provided 2017-10-04 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001270881 SCV001451659 uncertain significance Alagille syndrome due to a JAG1 point mutation 2020-06-15 criteria provided, single submitter clinical testing The JAG1 c.5G>T (p.Arg2Leu) variant is a missense variant. A literature search was conducted for the gene, cDNA change, and amino acid change. No publications were identified through this search. This variant is reported at a frequency of 0.000045 in the Total population from the Genome Aggregation Database, though this is based on two alleles in a region of good sequencing coverage in genomes so the variant is presumed to be rare. The arginine at position two is part of the signal peptide domain, which is involved in trafficking of the protein to the correct subcellular location. In silico algorithms differ in their predicted functional consequence of this variant, and its effect has not been investigated experimentally. Based on the limited evidence available, the p.Arg2Leu variant is classified as a variant of uncertain significance for Alagille syndrome.
Labcorp Genetics (formerly Invitae), Labcorp RCV001270881 SCV001513941 benign Alagille syndrome due to a JAG1 point mutation 2024-01-07 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002499351 SCV002806188 uncertain significance 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 2022-02-04 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004547925 SCV004113089 uncertain significance JAG1-related disorder 2023-03-08 criteria provided, single submitter clinical testing The JAG1 c.5G>T variant is predicted to result in the amino acid substitution p.Arg2Leu. This variant has been reported in the heterozygous state in an individual with congenital hypogonadotropic hypogonadism (CHH) (Cotellessa L et al. 2023, DOI: 10.1172/jci.insight.161998, https://insight.jci.org/articles/view/161998). This variant is reported in 0.12% (1/866) of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-10654174-C-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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