Submissions for variant NM_000214.3(JAG1):c.1339T>C (p.Cys447Arg)

dbSNP: rs863223651

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196545	SCV000250459	likely pathogenic	not provided	2015-05-29	criteria provided, single submitter	clinical testing	C447R is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. C447R is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function.This variant was found in JAG1
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223845	SCV000280108	uncertain significance	not specified	2014-07-15	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. JAG1 p.Cys447Arg This is a completely novel variant and it has not been previously reported in association with disease or as a benign polymorphism in controls. We classify it as a variant of unknown significance (VUS), probably disease-causing, concluding that there is not yet sufficient evidence for its pathogenicity. This is a nonconservative amino acid change, resulting in the replacement of a polar Cysteine with a positively-charged Arginine that cannot form disulfide bonds, at a location important for protein structure. It falls within EGF-like domain 6. Cysteine at this location is absolutely conserved across 10 vertebrate species for which there is sequence data. The adjacent residues are also absolutely conserved. Of note: Based on the conserved structure of these EGF-like repeats, which have 6 Cysteine residues that form disulfide bonds with one another, Cysteine 447 is predicted to form a disulfide bond with Cysteine 438. It is therefore significant that disrupting this bond by changing Cys438 has been associated with sporadic Alagille syndrome in a patient with a de novo Cys438Phe variant (Crosnier et al. 1999). Variation at another conserved Cysteine residue in EGF-like domain 6 has also been associated with Alagille syndrome, which supports the functional importance of these conserved Cysteine residues: Cys436Trp (Vozzi et al. 2013; HGMD professional version as of July 15, 2014). In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 1.0. In total the variant has not been seen in 6500 individuals from publicly available population datasets. There is no variation at this residue listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. Our patient’s ancestry is Caucasian. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also no variation at this residue listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or 1000 Genomes (http://browser.1000genomes.org/index.htm) as of July 15, 2014.