ClinVar Miner

Submissions for variant NM_002230.4(JUP):c.647G>A (p.Arg216Gln) (rs782498980)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000645203 SCV000766945 uncertain significance Naxos disease; Arrhythmogenic right ventricular cardiomyopathy, type 12 2018-06-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 216 of the JUP protein (p.Arg216Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs782498980, ExAC 0.002%). This variant has not been reported in the literature in individuals with JUP-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786328 SCV000925103 uncertain significance not provided 2017-10-25 no assertion criteria provided provider interpretation Found in a Caucasian teenager with a new diagnosis of HCM and a long history of prolonged QTc intervals. He had a 130-gene Arrhythmia and Cardiomyopathy Comprehensive Panel with the Invitae laboratory. Results included 4 variants: -p.Arg187Leu (c.560G>T) in the DOLK gene -p.Leu691Phe (c.2071C>T) in the DSP gene -p.Gly1546Ser (c.4636G>A) in the FLNC gene -p.Arg216Gln (c.647G>A) in the JUP gene p.Arg216Gln (c.647G>A) in exon 4 of the JUP gene (NM_002230.2, ENST00000393931.7) Chromosome location 17:39925281 C / T Based on the information reviewed below, we classify this as a Variant of Uncertain Significance, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has not previously been reported in the literature in association with disease, according to the Invitae report. The JUP gene is associated with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) (MedGen UID: 409749) and autosomal recessive Naxos disease (MedGen UID: 321991). This is not consistent with our patient's clinical evaluation. This is a nonconservative amino acid change, resulting in the replacement of a positively-charged Arginine with a polar Glutamine. Arginine at this location is highly conserved across ~100 vertebrate species for which we have data. The adjacent residues are also well conserved. There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In ExAC, Daniel MacArthur’s group from the Broad Institute has created a “constraint metric” for loss of function, indicating how tolerant each gene appears to be to heterozygous variants that lead to nonsense, splice acceptor, and splice donor variants that dramatically alter the protein. They call this pLI (Probability of LoF Intolerance). The closer the pLI is to 1, the more intolerant the gene appears to be. The pLI for the JUP gene is 0.04, meaning that it appears to be quite tolerant of heterozygous loss-of-function variants. However, of the variants in JUP that are listed in ClinVar as Likely Pathogenic or Pathogenic, approximately half are frameshift or nonsense variants (in the setting of recessive Naxos disease). This variant was reported in 2 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 2 non-Finnish European individuals (for the highest allele frequency: 0.002%), and overall MAF in gnomAD 0.001%. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.The curators made an effort to exclude individuals with severe pediatric diseases.

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