Submissions for variant NM_001360.3(DHCR7):c.385_412+5del

dbSNP: rs746482788

Total submissions: 9

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
Eurofins Ntd Llc (ga)	RCV000734341	SCV000862472	pathogenic	not provided	2018-07-23	criteria provided, single submitter	clinical testing
Invitae	RCV000411588	SCV000945030	pathogenic	Smith-Lemli-Opitz syndrome	2024-01-22	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Fulgent Genetics, Fulgent Genetics	RCV000411588	SCV002791622	pathogenic	Smith-Lemli-Opitz syndrome	2021-09-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000734341	SCV003805469	pathogenic	not provided	2023-02-22	criteria provided, single submitter	clinical testing	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)
Baylor Genetics	RCV000411588	SCV004041050	pathogenic	Smith-Lemli-Opitz syndrome	2023-03-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003401384	SCV004119144	likely pathogenic	DHCR7-related disorder	2023-07-17	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics, University Hospital of Duesseldorf	RCV000411588	SCV004171160	pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	not provided