Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001377820 | SCV001575255 | likely pathogenic | Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q | 2023-12-27 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 6 of the ERCC4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ERCC4 are known to be pathogenic (PMID: 9580660). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ERCC4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1066740). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003226467 | SCV003922956 | likely pathogenic | Xeroderma pigmentosum | 2023-03-17 | criteria provided, single submitter | clinical testing | Variant summary: ERCC4 c.1102+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 248688 control chromosomes (gnomAD). c.1102+1G>T has been reported in the literature in one individual affected with lung cancer. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites this variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |