ClinVar Genomic variation as it relates to human health

Variant summary: DHCR7 c.1054C>T (p.Arg352Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 275158 control chromosomes (gnomAD). The variant, c.1054C>T, has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (Fitzky_1998, Witsch-Baumgartner_2001, Waterham_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence showing more than 90% reduction in protein expression associated with this variant (Fitzky_1998). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Expression studies found that this variant is associated with significantly decreased DHCR7 protein expression (Fitzky BU et al., 1998); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10602371, 15952211, 16207203, 18006960, 16983147, 21696385, 17441222, 16044199, 20301322, 31840946, 22975760, 11175299, 15521979, 9653161, 25040602, 23042628)

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 352 of the DHCR7 protein (p.Arg352Trp). This variant is present in population databases (rs80338860, gnomAD 0.004%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 9653161, 15521979, 18006960; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 6787). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DHCR7 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects DHCR7 function (PMID: 9653161). This variant disrupts the p.Arg352 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16044199, 17441222, 21696385). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The DHCR7 c.1054C>T variant is predicted to result in the amino acid substitution p.Arg352Trp. This variant has been reported alone or with a second DHCR7 variant in individuals with Smith-Lemli-Opitz syndrome (see for example, Fitzky et al 1998. PubMed ID: 9653161; Witsch-Baumgartner et al 2001. PubMed ID: 11175299; Pappu et al 2006. PubMed ID: 16983147). In vitro experimental studies suggest this variant impacts protein function (Fitzky et al 1998. PubMed ID: 9653161). Alternative nucleotide changes affecting the same amino acid (p.Arg352Gln, p.Arg352Leu) have also been reported in individuals with Smith-Lemli-Opitz syndrome (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299; Al-Owain et al. 2012. PubMed ID: 21696385). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.