ClinVar Genomic variation as it relates to human health

The DHCR7 c.1A>G; p.Met1? variant (rs104886033) is reported in the literature in multiple individuals affected with Smith-Lemli-Opitz syndrome (SLOS) (Bianconi 2011, Pappu 2006, Scalco 2005, Witsch-Baumgartner 2005). Most affected individuals with this variant were described with mild disease and were found to carry an additional pathogenic variant in trans (Bianconi 2011, Pappu 2006, Scalco 2005, Witsch-Baumgartner 2005). The c.1A>G variant is found on only four chromosomes (4/282880 alleles) in the Genome Aggregation Database. This variant abolishes the canonical start codon, which is likely to negatively impact gene function. While a DHCR7 protein beginning at the next downstream methionine, Met59, has been demonstrated to be enzymatically active (Wassif 2005), it is unknown if this downstream methionine is used in vivo or how the activity compares to the canonical protein. Another variant affecting the canonical methionine (c.3G>A) has also been reported in individuals affected with SLOS and is considered disease-causing (Waterham 2000). Based on available information, the c.1A>G variant is considered to be pathogenic. References: Bianconi SE et al. Adrenal function in Smith-Lemli-Opitz syndrome. Am J Med Genet A. 2011 Nov;155A(11):2732-8. Pappu AS et al. Increased nonsterol isoprenoids, dolichol and ubiquinone, in the Smith-Lemli-Opitz syndrome: effects of dietary cholesterol. J Lipid Res. 2006 Dec;47(12):2789-98. Scalco FB et al. DHCR7 mutations in Brazilian Smith-Lemli-Opitz syndrome patients. Am J Med Genet A. 2005 Jul 30;136(3):278-81. Wassif CA et al. Mutations in the human sterol delta7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. Am J Hum Genet. 1998 Jul;63(1):55-62. Waterham HR and Wanders RJ. Biochemical and genetic aspects of 7-dehydrocholesterol reductase and Smith-Lemli-Opitz syndrome. Biochim Biophys Acta. 2000 Dec 15;1529(1-3):340-56. Witsch-Baumgartner M et al. Identification of 14 novel mutations in DHCR7 causing the Smith-Lemli-Opitz syndrome and delineation of the DHCR7 mutational spectra in Spain and Italy. Hum Mutat. 2005 Apr;25(4):412.

PM2, PS1, PS4, PVS1

This sequence change affects the initiator methionine of the DHCR7 mRNA. The next in-frame methionine is located at codon 59. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of the initiator codon has been observed in individuals with Smith-Lemli-Opitz syndrome (PMID: 12949967, 15776424, 15952211, 16983147, 21990131). ClinVar contains an entry for this variant (Variation ID: 6794). For these reasons, this variant has been classified as Pathogenic.

The alteration results in an initiation codon change: _x000D_ _x000D_ The c.1A>G (p.M1?) alteration is located in exon 3 (coding exon 1) of the DHCR7 gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Sequence variations that modify the initiation codon (ATG) are typically deleterious in nature as they are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. However, there is an in-frame methionine 59 amino acids downstream, which may act as an alternative initiation codon and result in an N-terminal truncation; however, direct evidence is unavailable and the significance of the N-terminus for this protein is not well established. The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.1A>G alteration was observed in 0.0014% (4/282880) of total alleles studied, with a frequency of 0.0023% (3/129192) in the European (non-Finnish) subpopulation. The alteration has been observed in affected individuals:_x000D_ _x000D_ The c.1A>G (p.M1?) alteration has been reported in multiple patients with a confirmed biochemical diagnosis of SLOS along with a second disease-causing mutation. Several patients have been reported to have mild clinical symptoms despite co-occuring with a severe allele (Bianconi, 2011; Eroglu, 2017; Scalco, 2005; Witsch-Baumgartner, 2004). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.M1 amino acid is conserved in available vertebrate species. Based on the available evidence, this alteration is classified as pathogenic.

This variant is associated with the following publications: (PMID: 15776424, 31589614, 9634533, 15952211, 12949967, 16983147, 22391996, 24500076, 21990131, 37644014)

Variant summary: The DHCR7 c.1A>G (p.Met1Val) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/121390 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). This variant has been reported in multiple compound heterozygous SLOS patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. The variant of interest affects the translational start sight, however, Scalco_2005 indicates that translational initiation at Methionine 59 produces a functional protein. Therefore, suggesting that this would help explain the mild phenotype observed in affected individuals. Taken together, this variant is classified as likely pathogenic.

The DHCR7 c.1A>G variant is predicted to disrupt the translation initiation site (Start loss). This variant, which is sometimes described in the literature as p.M1V, has been reported in multiple individuals with Smith-Lemli-Opitz syndrome (Witsch-Baumgartner et al. 2005. PubMed ID: 15776424; Pappu et al. 2006. PubMed ID: 16983147; Bianconi et al. 2011. PubMed ID: 21990131). This variant is reported in 0.0028% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.