ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.385_412+5del (rs746482788)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411588 SCV000485776 likely pathogenic Smith-Lemli-Opitz syndrome 2016-02-16 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000734341 SCV000862472 pathogenic not provided 2018-07-23 criteria provided, single submitter clinical testing
Invitae RCV000411588 SCV000945030 likely pathogenic Smith-Lemli-Opitz syndrome 2019-09-23 criteria provided, single submitter clinical testing This variant is a deletion of the genomic region encompassing part of exon 5 (c.385_412+5del) of the DHCR7 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with DHCR7-related disease. ClinVar contains an entry for this variant (Variation ID: 370449). Loss of function variants in DHCR7 are known to be pathogenic (PMID: 10677299, 9634533, 15776424). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000411588 SCV001362512 pathogenic Smith-Lemli-Opitz syndrome 2019-07-07 criteria provided, single submitter clinical testing 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.

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