Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000480811 | SCV000573548 | likely pathogenic | not provided | 2017-03-06 | criteria provided, single submitter | clinical testing | The c.224+5 G>C variant in the CHKB gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.224+5 G>C 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). Several in-silico splice prediction models predict that c.224+5 G>C destroys the natural splice donor site for intron 1 which may lead to abnormal gene splicing. This variant occurs at a position that is conserved across species. In summary, we interpret c.224+5 G>C to be a likely pathogenic variant. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. |
| Labcorp Genetics |
RCV001245358 | SCV001418641 | uncertain significance | Megaconial type congenital muscular dystrophy | 2023-08-28 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 423804). This variant has not been reported in the literature in individuals affected with CHKB-related conditions. This variant is present in population databases (rs765251030, gnomAD 0.003%). This sequence change falls in intron 1 of the CHKB gene. It does not directly change the encoded amino acid sequence of the CHKB protein. It affects a nucleotide within the consensus splice site. 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. 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. |
| Undiagnosed Diseases Network, |
RCV001245358 | SCV001432144 | uncertain significance | Megaconial type congenital muscular dystrophy | 2018-03-06 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV004975567 | SCV005554066 | likely pathogenic | Inborn genetic diseases | 2024-06-27 | criteria provided, single submitter | clinical testing | The c.224+5G>C intronic alteration results from a G to C substitution 5 nucleotides after coding exon 1 of the CHKB gene. Based on data from gnomAD, the C allele has an overall frequency of 0.002% (4/258836) total alleles studied. The highest observed frequency was 0.004% (4/114784) of European (non-Finnish) alleles. This variant has been identified in conjunction with another CHKB variant in an individual with features consistent with megaconial type congenital muscular dystrophy (Undiagnosed Diseases Network, Participant 086). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as likely pathogenic. |
| Department of Pathology and Laboratory Medicine, |
RCV001245358 | SCV006055241 | uncertain significance | Megaconial type congenital muscular dystrophy | 2022-07-04 | criteria provided, single submitter | research |