Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000809686 | SCV000949852 | likely pathogenic | Ataxia-telangiectasia syndrome | 2018-10-12 | criteria provided, single submitter | clinical testing | Nucleotide substitutions within 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 and strengthen a cryptic acceptor site in exon 63, located 13 nucleotides downstream of the natural splice site. Additionally, an experimental study has reported that disruption of this splice site (c.8988-1G>C) results in the loss of 13 nucleotides from exon 63, causing a frameshift at codon 2996 (p.Ser2996Argfs*6) (PMID: 10330348). Disruption of this splice site has been observed to be homozygous or on the opposite chromosome (in trans) from a pathogenic variant in individuals affected with ataxia-telangiectasia (PMID: 27664052, 12815592). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 185326). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in the last intron (intron 62) of the ATM gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. 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. |