Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001235655 | SCV001408349 | likely pathogenic | Smith-Lemli-Opitz syndrome | 2022-10-01 | criteria provided, single submitter | clinical testing | 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: 961893). Disruption of this splice site has been observed in individual(s) with Smith–Lemli–Opitz syndrome (PMID: 23042628, 25734025). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change affects a splice site in intron 3 of the DHCR7 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 DHCR7 are known to be pathogenic (PMID: 9634533, 10677299). 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, |
RCV001235655 | SCV001623357 | likely pathogenic | Smith-Lemli-Opitz syndrome | 2021-04-20 | criteria provided, single submitter | clinical testing | Variant summary: DHCR7 c.98+2_98+6delTAAGG 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: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251496 control chromosomes. c.98+2_98+6delTAAGG has been reported in the literature in at-least one individual affected with Smith-Lemli-Opitz Syndrome and has been subsequently cited by others (example, Waterham_2012, Bianconi_2015). 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 clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic citing an overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. |