ClinVar Genomic variation as it relates to human health

Variant summary: DHCR7 c.385_412+5del33 is located to span 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: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing demonstrating an altered product that fails to amplify upon RT-PCR presumably due to an unstable mRNA (De Brasi_1999). The variant allele was found at a frequency of 4.4e-05 in 247546 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (4.4e-05 vs 0.0043), allowing no conclusion about variant significance. c.385_412+5del33 has been reported in the literature in at-least one individual affected with Smith-Lemli-Opitz Syndrome (De Brasi_1999). Two 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 (n=1)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

This variant results in the deletion of part of exon 5 (c.385_412+5del) of the DHCR7 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DHCR7 are known to be pathogenic (PMID: 9634533, 10677299). This variant is present in population databases (rs746482788, gnomAD 0.007%). This variant has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10602371). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 384-IVS5+4 del. ClinVar contains an entry for this variant (Variation ID: 370449). For these reasons, this variant has been classified as Pathogenic.

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23042628, 10602371)

The DHCR7 c.385_412+5del33 variant is predicted to result in a deletion affecting a canonical splice site. This variant, also described as 384–IVS5 + 4 del, was reported in the compound heterozygous state in an individual with Smith-Lemli-Opitz syndrome (De Brasi et al 1999. PubMed ID: 10602371). No aberrant mRNA product was obtained by reverse transcriptase-PCR using primers near the c.385_412+5del33 variant suggesting this variant affects splicing, possibly through nonsense mediated decay (De Brasi et al 1999. PubMed ID: 10602371). This variant is reported in 0.0080% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-71153303-GGCTACCTGCAGGAGTCACGGCCCCCTCCTGGAT-G). This variant is interpreted as likely pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Smith-Lemli-Opitz syndrome (MIM#270400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Exceptionally mild and severe cases have been reported, with intrafamilial and interfamilial variable expressivity (PMID: 35305950, 20301322). (I) 0211 - Canonical splice site variant without proven consequence on splicing. RT-PCR studies have been undertaken on this variant but the data was not shown in the paper and the interpretation of the results was unclear (PMID: 10602371). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (11 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0704 - Another smaller deletion variant comparable to the one identified in this case has limited previous evidence for pathogenicity. c.390_412+3del has been observed along with a second DHCR7 variant in two individuals with SLOS (PMID: 22211794). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic or pathogenic by multiple clinical laboratories in ClinVar, and has been observed as compound heterozygous in two individuals with SLOS in the literature (PMIDs: 17497248, 10602371). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign