ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.964-1G>T (rs138659167)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000383519 SCV000793446 pathogenic Smith-Lemli-Opitz syndrome 2017-08-16 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000383519 SCV000373913 likely pathogenic Smith-Lemli-Opitz syndrome 2017-04-27 criteria provided, single submitter clinical testing The DHCR7 c.964-1G>T variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.964-1G>T variant, which is also described as IVS8-1G>T, has been reported in two studies in which it is identified in three patients with Smith-Lemli-Opitz syndrome (SLOS), including one homozygote and two compound heterozygotes (Jira et al. 2001; Weaver et al. 2008; Lanthaler et al. 2013). This variant was also found in a heterozygous state in the father of one patient, who had abnormally low cholesterol levels. Control data are unavailable for this variant, which is reported at a frequency of 0.00666 in the European (Finnish) population of the Exome Aggregation Consortium database. Jira et al. (2001) noted that the c.964-1G>T variant occurs at the same position as the known pathogenic c.964-1G>C splice acceptor variant, which accounts for over 28% of all disease-causing alleles in SLOS. The c.964-1G>C variant disrupts the splice acceptor site of intron eight, which leads to the insertion of 134 base pairs of intronic sequence into the DHCR7 mRNA causing a frameshift and premature truncation, ultimately resulting in a non-functional protein product. The c.964-1G>T variant is predicted to result in the same non-functional protein. Based on the evidence and due to the potential impact of splice acceptor variants, the c.964-1G>T variant is classified as likely pathogenic for Smith-Lemli-Opitz syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000383519 SCV000917276 pathogenic Smith-Lemli-Opitz syndrome 2018-11-29 criteria provided, single submitter clinical testing Variant summary: DHCR7 c.964-1G>T is located in 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: Five predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.6e-05 in 259000 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (6.6e-05 vs 0.0043), allowing no conclusion about variant significance. The variant, c.964-1G>T, has been reported in the literature in compound heterozygote and homozygote individuals affected with Smith-Lemli-Opitz Syndrome (Jira_2001, Weaver_2010, Lanthaler_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000383519 SCV000832154 pathogenic Smith-Lemli-Opitz syndrome 2018-02-08 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in the last intron (intron 8) of the DHCR7 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs138659167, ExAC 0.07%). This variant has been reported in individuals affected with Smith–Lemli–Opitz Syndrome (PMID: 11427181, 20104611). It is also known as IVS8-1G>T. ClinVar contains an entry for this variant (Variation ID: 305956). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. A different variant affecting this nucleotide (c.964-1G>C) has been determined to be pathogenic (PMID: 23042628, 10814720, 10995508, 11427181). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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