ClinVar Genomic variation as it relates to human health

The DHCR7 c.964-1G>T variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.964-1G>T variant, which is also described as IVS8-1G>T, has been reported in two studies in which it is identified in three patients with Smith-Lemli-Opitz syndrome (SLOS), including one homozygote and two compound heterozygotes (Jira et al. 2001; Weaver et al. 2008; Lanthaler et al. 2013). This variant was also found in a heterozygous state in the father of one patient, who had abnormally low cholesterol levels. Control data are unavailable for this variant, which is reported at a frequency of 0.00666 in the European (Finnish) population of the Exome Aggregation Consortium database. Jira et al. (2001) noted that the c.964-1G>T variant occurs at the same position as the known pathogenic c.964-1G>C splice acceptor variant, which accounts for over 28% of all disease-causing alleles in SLOS. The c.964-1G>C variant disrupts the splice acceptor site of intron eight, which leads to the insertion of 134 base pairs of intronic sequence into the DHCR7 mRNA causing a frameshift and premature truncation, ultimately resulting in a non-functional protein product. The c.964-1G>T variant is predicted to result in the same non-functional protein. Based on the evidence and due to the potential impact of splice acceptor variants, the c.964-1G>T variant is classified as likely pathogenic for Smith-Lemli-Opitz syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Variant summary: DHCR7 c.964-1G>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: Five predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.6e-05 in 259000 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (6.6e-05 vs 0.0043), allowing no conclusion about variant significance. The variant, c.964-1G>T, has been reported in the literature in compound heterozygote and homozygote individuals affected with Smith-Lemli-Opitz Syndrome (Jira_2001, Weaver_2010, Lanthaler_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.

This sequence change affects an acceptor splice site in intron 8 of the DHCR7 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs138659167, gnomAD 0.05%). Disruption of this splice site has been observed in individuals with Smith–Lemli–Opitz Syndrome (PMID: 11427181, 20104611). ClinVar contains an entry for this variant (Variation ID: 305956). 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. This variant disrupts the c.964-1G nucleotide in the DHCR7 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10814720, 10995508, 11427181, 23042628). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The DHCR7 c.964-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in an individual with Smith-Lemli-Opitz syndrome (described as IVS8-1G>T, Jira et al. 2001. PubMed ID: 11427181). This variant is reported in 0.051% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-71146886-C-A). Variants that disrupt the consensus splice acceptor site in DHCR7 are expected to be pathogenic. This variant is interpreted as pathogenic.

The c.964-1G>T intronic alteration consists of a G to T substitution one nucleotide before coding exon 7 of the DHCR7 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (17/262084) total alleles studied. The highest observed frequency was 0.05% (10/19724) of European (Finnish) alleles. This variant has been reported in the homozygous and compound heterozygous states in patients with Smith-Lemli-Opitz syndrome (SLOS) (Jira, 2001; Weaver, 2010; Lanthaler, 2013). In addition, another variant at this position (c.964-1G>C) is one of the most common DHCR7 mutations associated with SLOS (Witsch-Baumgartner, 2008). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic.

Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 28166604, 11427181, 23042628, 20104611, 9653161, 21777499, 22929031)