ClinVar Genomic variation as it relates to human health

The c.452G>A (p.Trp151Ter) variant is a well-described, common stop-gained variant that accounts for 6.0% of variant DHCR7 alleles (Correa-Cerro et al. 2005a; Nowaczyk et al. 2013). Across a selection of the available literature, the p.Trp151Ter variant has been identified in at least 62 patients with Smith-Lemli-Opitz syndrome, including eight in a homozygous state and 54 in a compound heterozygous state. The p.Trp151Ter variant was also identified in a heterozygous state in 39 unaffected Polish neonates (Fitzky et al. 1998; Witsch-Baumgartner et al. 2000; Krakowiak et al. 2000; Löffler et al. 2000; Witsch-Baumgartner et al. 2001; Ciara et al. 2004; Correa-Cerro et al. 2005; Ciara et al. 2006; Kolejáková et al. 2009). The p.Trp151Ter variant was absent from 80 control individuals but is reported at a frequency of 0.00116 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated an absence of protein and no enzyme activity in HEK cells transfected with the variant (Witsch-Baumgartner et al. 2000). Correa-Cerro et al. (2005b) demonstrated that the p.Trp151Ter variant undergoes nonsense mediated decay. Haplotype analysis indicates the p.Trp151Ter variant occurs on three related haplotypes and appears to have originated in southern Poland (Witsch-Baumgartner et al. 2001; Correa-Cerro et al 2005a). Due to the potential impact of stop-gained variants and the supporting evidence from the literature, the p.Trp151Ter variant is classified as pathogenic for Smith-Lemli-Opitz syndrome.

Variant summary: The DHCR7 c.452G>A (p.Trp151X) variant results in a premature termination codon, predicted to cause a absent DHCR7 protein due to nonsense mediated decay, which is known mechanisms for disease. This prediction has been confirmed by a study using DNA and RNA level analysis which showed that mRNA derived from blood leukocytes carrying the variant of interest lacks the p. Trp151 * allele (Balogh_MS_2012). This variant was found in 82/120858 control chromosomes at a frequency of 0.0006785, which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). It was reported in several SLOS patients in either homozygosity or compound heterozygosity with other pathogenic DHCR7 alleles indicating pathogenicity. Moreover, several clinical diagnostic laboratories classify variant as pathogenic. The variant is one of the most common SLOS-causing mutations with prevalence amongst affected individuals ranging from 2.3% to 50% deepening on the population studied. Taken together, this variant is classified as pathogenic.

NM_001360.2(DHCR7):c.452G>A(W151*) is classified as pathogenic in the context of Smith-Lemli-Opitz syndrome and is associated with the severe form of the disease. Sources cited for classification include the following: PMID 9653161, 20556518, and 10677299. Classification of NM_001360.2(DHCR7):c.452G>A(W151*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PS3,PP4,PM3.

Reported previously in association with Smith-Lemli-Opitz syndrome (SLOS), in affected individuals who are compound heterozygous for the W151X variant and another pathogenic variant, and has been observed in the homozygous state in a lethal form of SLOS (Fitzky et al., 1998; Correa-Cerro et al., 2005b; Loffler et al., 2000); Studies of patient fibroblasts demonstrated that the transcript with this variant underwent nonsense-mediated mRNA decay in a gene for which loss-of-function is a known mechanism of disease (Correa-Cerro et al., 2005b); This variant is associated with the following publications: (PMID: 10995508, 25525159, 29300326, 27415407, 19390132, 22975760, 11175299, 16687448, 16678134, 15805162, 11078571, 27066502, 26685159, 9653161, 28166604, 29165578, 28250423, 15521979, 16497572, 20556518, 23293579, 10677299, 17965227, 29433144, 30609409, 31980526, 31589614)

PVS1, PM2, PP3, PP5

This sequence change creates a premature translational stop signal (p.Trp151*) in the DHCR7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DHCR7 are known to be pathogenic (PMID: 9634533, 10677299). This variant is present in population databases (rs11555217, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with Smith-Lemli-Opitz syndrome (PMID: 9653161, 11078571, 11175299, 15521979, 16497572, 17965227, 19390132). ClinVar contains an entry for this variant (Variation ID: 21273). For these reasons, this variant has been classified as Pathogenic.

DHCR7: PM3:Very Strong, PVS1, PM2

The p.Trp151X (NM_001360.2 c.452G>A) variant in DHCR7 has been reported in sever al individuals with Smith-Lemli-Opitz syndrome. Most of these individuals were c ompound heterozygous for the variant (Fitzky 1998, Correa-Cerro 2005). This vari ant has also been reported in ClinVar (Variation ID#21273), as pathogenic by mul tiple laboratories. It has been identified in 0.13% (174/125,000) of European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs11555217). Although this variant has been seen in the general p opulation, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at posi tion 151 which is predicted to lead to a truncated or absent protein. Biallelic loss of function of the DHCR7 gene is associated with Smith-Lemli-Opitz syndrome . In summary, this variant meets our criteria to be classified as pathogenic f or Smith-Lemli-Opitz syndrome in an autosomal recessive manner based on its occu rrence in individuals with this disease and a predicted null effect.

The variant was confirmed as compound heterozygous with a pathogenic variant (NM_001163817.1: c.964-1G>C).

This sequence change in DHCR7 is a nonsense variant predicted to cause a premature stop codon, p.(Trp151*), in biologically-relevant-exon 6/9 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (ClinGen). The highest population minor allele frequency in gnomAD v2.1 is 0.1% (181/127,446 alleles) in the European (non-Finnish) population. This variant has been detected in at least 25 individuals with Smith-Lemli Opitz syndrome (SLOS), many with biochemical confirmation indicated by elevated 7-dehydrocholesterol. Of those individuals, two individuals were homozygous and 18 were compound heterozygous for the variant and a pathogenic variant and two of those were confirmed in trans by parental testing. The variant has been reported to segregate with SLOS in at least three families (PMID: 9653161, 11078571, 15521979). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong, PP1_Strong, PP4.

The c.452G>A (p.W151*) alteration, located in exon 6 (coding exon 4) of the DHCR7 gene, consists of a G to A substitution at nucleotide position 452. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 151. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This recurrent mutation has been documented to account for 6.9% of mutant alleles in DHCR7 and has been reported in the homozygous state and in trans with a second DHCR7 alteration in multiple patients with Smith Lemli Opitz syndrome (SLOS) (Fitzky, 1998; Witsch-Baumgartner, 2000; Löffler, 2000; Krakowiak, 2000; Lazarin, 2017). In addition, this was the second most commonly seen mutation on carrier screens elected from 2012-2015 (Lazarin, 2013). One study found that the carrier frequency of this mutation in Ashkenazi Jewish individuals may be as high as 1/40 and 1/122 in non-Ashkenazi Jewish individuals (Shi, 2017). Based on the available evidence, this alteration is classified as pathogenic.

The DHCR7 c.452G>A variant is predicted to result in premature protein termination (p.Trp151*). This variant has been reported to be causative for Smith-Lemli-Opitz syndrome (SLOS) (Fitzky et al. 1998. PubMed ID: 9653161; Witsch-Baumgartner et al. 2001. PubMed ID: 11175299; Waterham and Hennekam. 2012. PubMed ID: 23042628). It is one of the most commonly reported causative DHCR7 variants among affected individuals of European descent (Witsch-Baumgartner et al. 2001. PubMed ID: 11175299; Ciara et al. 2006. PubMed ID: 16497572; Witsch-Baumgartner et al. 2008. PubMed ID: 17965227). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in DHCR7 are expected to be pathogenic. This variant is interpreted as pathogenic.

The heterozygous variant in the DHCR7 gene (c.452G>A; p.Trp151Term) is considered pathogenic as this variant has been previously published in multiple affected individuals and is the third most common DHCR7 mutation (Correa-Cerro et al. 2013; PMID: 15670717; Witsch-Baumgartner et al. 200; PMID: 10677299; Löffler et al 2000, PMID: 11078571).

Variant identified in multiple participants. Variant interpreted as Pathogenic and reported, most recently, on 11-13-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.