ClinVar Genomic variation as it relates to human health

The DHCR7 c.1066delC; p.His356fs variant (rs774291653), to our knowledge, is not reported in the medical literature or gene specific databases in association with Smith-Lemli-Opitz syndrome. This variant is reported in ClinVar (Variation ID: 370598), and is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the DHCR7 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein that would include a sequence of 57 amino acid residues not usually present. Additionally, several downstream truncating variants have been described in individuals with Smith-Lemli-Opitz syndrome and are considered pathogenic (Cross 2015, Jong Hee Chae 2007, Yan 2019). Based on available information, the p.His356fs variant is considered to be pathogenic. References: Cross JL et al. Determination of the allelic frequency in Smith-Lemli-Opitz syndrome by analysis of massively parallel sequencing data sets. Clin Genet. 2015 Jun;87(6):570-5. Jong Hee Chae et al. Identification of a novel DHCR7 mutation in a Korean patient with Smith-Lemli-Opitz syndrome. J Child Neurol. 2007 Nov;22(11):1297-300. Yan H et al. Targeted next generation sequencing in 112 Chinese patients with intellectual disability/developmental delay: novel mutations and candidate gene. BMC Med Genet. 2019 May 14;20(1):80.

This sequence change creates a premature translational stop signal (p.His356Thrfs*57) in the DHCR7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 120 amino acid(s) of the DHCR7 protein. This variant is present in population databases (rs774291653, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with DHCR7-related conditions. ClinVar contains an entry for this variant (Variation ID: 370598). This variant disrupts a region of the DHCR7 protein in which other variant(s) (p.Lys376Argfs*37) have been determined to be pathogenic (PMID: 18006960). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Variant summary: DHCR7 c.1066delC (p.His356ThrfsX57) results in a premature termination codon, predicted to cause a truncation of the encoded protein. Although, nonsense mediated decay is not predicted, several pathogenic variants are observed downstream. The variant allele was found at a frequency of 1.6e-05 in 249058 control chromosomes. To our knowledge, no occurrence of c.1066delC in individuals affected with Smith-Lemli-Opitz Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 370598). Based on the evidence outlined above, the variant was classified as pathogenic.

The DHCR7 c.1066delC variant is predicted to result in a frameshift and premature protein termination (p.His356Thrfs*57). To our knowledge, this variant has not been reported in the literature in any affected individuals. This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is not expected to lead to nonsense-mediated mRNA decay (NMD), but it is predicted to disrupt the terminal 120 amino acids of the DHCR7 protein. Loss-of-function variants up- and downstream of this variant have been reported in association with Smith-Lemli-Opitz syndrome (SLOS), as have missense variants occurring in the terminal 120 amino acids of DHCR7 (Human Gene Mutation Database). Taken together, the c.1066delC (p.His356Thrfs*57) variant is interpreted as likely pathogenic.