Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001208428 | SCV001379815 | likely pathogenic | Naxos disease; Arrhythmogenic right ventricular dysplasia 12 | 2023-04-20 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 212749). This variant has been observed in individuals with clinical features of autosomal recessive Naxos disease (PMID: 20130592, 32212272). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects codon 156 of the JUP mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the JUP protein. This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. |
| Ambry Genetics | RCV002336520 | SCV002636353 | uncertain significance | Cardiovascular phenotype | 2019-10-15 | criteria provided, single submitter | clinical testing | The c.468G>A variant (also known as p.P156P), located in coding exon 2 of the JUP gene, results from a G to A substitution at nucleotide position 468. This nucleotide substitution does not change the proline at codon 156, but this variant occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in the homozygous state in four siblings from one family with cutaneous disease; their heterozygous parents were unaffected (Boente Mdel C et al. Br. J. Dermatol., 2016 Sep;175:644-6; Cabral RM et al. J. Invest. Dermatol., 2010 Jun;130:1543-50). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site. However, although loss of function of JUP is pathogenic with respect to autosomal recessive disease, loss of function has not been clearly established as a mechanism of disease for autosomal dominant arrhythmogenic right ventricular cardiomyopathy (AD ARVC). Since evidence supporting a role for this alteration in AD ARVC is limited at this time, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV001208428 | SCV002780795 | uncertain significance | Naxos disease; Arrhythmogenic right ventricular dysplasia 12 | 2021-10-28 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000192505 | SCV000249575 | pathogenic | Naxos disease | 2010-06-01 | no assertion criteria provided | literature only |