ClinVar Miner

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

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623789 SCV000741293 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Ambry Genetics RCV000717414 SCV000848264 pathogenic History of neurodevelopmental disorder 2018-01-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without splicing assay data in support of pathogenicity,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,Deficient protein function by in vitro/ex vivo assay
Athena Diagnostics Inc RCV000079661 SCV000613096 pathogenic not provided 2016-04-13 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000079661 SCV000281572 pathogenic not provided 2015-01-30 criteria provided, single submitter clinical testing
Counsyl RCV000180570 SCV000678031 pathogenic Smith-Lemli-Opitz syndrome 2015-06-13 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000180570 SCV000745303 pathogenic Smith-Lemli-Opitz syndrome 2016-01-25 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000180570 SCV000733106 pathogenic Smith-Lemli-Opitz syndrome no assertion criteria provided clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000180570 SCV000536751 pathogenic Smith-Lemli-Opitz syndrome 2015-07-23 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079661 SCV000233039 pathogenic not provided 2017-01-12 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000180570 SCV000803783 likely pathogenic Smith-Lemli-Opitz syndrome 2017-10-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000180570 SCV000611262 pathogenic Smith-Lemli-Opitz syndrome 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000079661 SCV000321549 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing The c.964-1 G>C variant in the DHCR7 gene has been reported previously in association with Smith-Lemli Opitz syndrome (SLOS) and is considered to be the most common pathogenic variant associated with SLOS among Caucasian individuals from North America and Western Europe (Fitzky et al., 1998; DeBarber et al., 2011). The c.964-1 G>C variant is observed in 342/50488 (0.68%) alleles from individuals of Non-Finnish European background in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). This splice site variant destroys the canonical splice acceptor site in intron 8, which is predicted to cause abnormal gene splicing. We interpret c.964-1 G>C as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000180570 SCV000247185 likely pathogenic Smith-Lemli-Opitz syndrome 2015-07-22 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000180570 SCV000743877 pathogenic Smith-Lemli-Opitz syndrome 2017-07-28 criteria provided, single submitter clinical testing
Gharavi Laboratory,Columbia University RCV000079661 SCV000809236 pathogenic not provided 2018-09-16 no assertion criteria provided research
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000180570 SCV000891754 pathogenic Smith-Lemli-Opitz syndrome 2018-06-22 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000180570 SCV000373914 pathogenic Smith-Lemli-Opitz syndrome 2016-06-14 criteria provided, single submitter clinical testing The c.964-1G>C variant, alternatively described as IVS8-1G>C, is well described in the literature and is the most common pathogenic variant for Smith-Lemli-Opitz syndrome accounting for at least 29% of all disease alleles (Witsch-Baumgartner et al. 2015). Across a selection of the available literature, the c.964-1G>C variant has been identified in 53 patients, including four in a homozygous state and 49 in a compound heterozygous state (including three pairs of siblings) (Waterham et al. 1998; Fitzky et al. 1998; Krakowiak et al. 2000; Yu et al. 2000; Jira et al. 2001; Balogh et al. 2012). Individuals who are homozygous for the variant manifest a severe and lethal phenotype while compound heterozygotes manifest a moderate to mild phenotype with the clinical severity of the disease dependent on the second allele. The variant was found in a heterozygous state in one of over 1,138 control alleles and is reported at a frequency of 0.01515 in the Utah Residents (CEPH) with Northern and Western Ancestry population of the 1000 Genomes Project. The c.964-1G>C occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. Functional analysis of the variant using RT-PCR in patient skin fibroblasts demonstrated that the variant causes aberrant mRNA splicing and insertion of 134 bp resulting in a frameshift that prematurely truncates the protein. The insertion occurs in a region strongly conserved among sterol reductases (Waterham et al. 1998). Based on the potential impact of splice acceptor variants and collective evidence from the literature, the c.964-1G>C is classified as pathogenic for Smith-Lemli-Opitz syndrome.
Integrated Genetics/Laboratory Corporation of America RCV000180570 SCV000697859 pathogenic Smith-Lemli-Opitz syndrome 2016-01-21 criteria provided, single submitter clinical testing
Invitae RCV000180570 SCV000630077 pathogenic Smith-Lemli-Opitz syndrome 2019-01-06 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 8 of the DHCR7 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is considered the most common pathogenic variant in the DHCR7 gene, and has been reported in approximately 30% of all individuals affected with Smith-Lemli-Opitz syndrome (PMID: 23042628, 10814720, 10995508, 11427181). It is also known as IVS8-1G>C in the literature. ClinVar contains an entry for this variant (Variant ID: 93725). An experimental study has shown that this variant results in the use of an alternative splice site, which inserts 134 nucleotides between exons 8 and 9 and causes a frameshift (PMID: 9653161). For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000180570 SCV000494249 pathogenic Smith-Lemli-Opitz syndrome 2016-07-18 criteria provided, single submitter clinical testing The c.964-1G>C splice variant in the DHCR7 gene has been previously reported in multiple individuals affected with Smith-Lemli-Opitz Syndrome (Witsch-Baumgartner et al., 2000; Jira et al., 2001; Fitzky et al., 1998; Krakowiak et al., 2000). In one individual, this variant was observed in trans with a known pathogenic variant, p.Pro51Leu (Fitzky et al., 1998). Furthermore, RT-PCR and sequencing of the variant transcript showed that this variant leads to the use of an alternative splice acceptor in intron 8, which results in the insertion of 134 bp of intronic sequence, and ultimately a frameshift and premature termination (Fitzky et al., 1998). Loss of function is a mechanism of disease for this condition, however, no pathogenic nonsense or splice variants have been reported in DHCR7 downstream of this variant. This variant is reported at significantly higher frequency in affected individuals than the general population (OR=108.9000 (14.51-817.55)) (Witsch-Baumgartner et al., 2000). Multiple in silico algorithms predict this variant to be conserved and deleterious (CADD = 19.68; GERP=5.08). Emory Genetics Laboratory has classified this variant as Pathogenic, and The Genetic Services Laboratory of the University of Chicago has classified it as Likely Pathogenic. DHCR7 is the only gene in which variants have been shown to cause Smith-Lemli-Opitz Syndrome. Therefore, this collective evidence supports the classification of the c.964-1G>C as a Pathogenic variant for Smith-Lemli-Opitz Syndrome. We have confirmed this finding in our laboratory using Sanger sequencing.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000180570 SCV000711716 pathogenic Smith-Lemli-Opitz syndrome 2015-12-08 criteria provided, single submitter clinical testing The c.964-1G>C variant in DHCR7 has been reported in >50 patients with Smith-Lem li-Opitz syndrome (SLO) who were either homozygous or compound heterozygous for this variant (Fitzky 1998, Krakowiak 2000, Witsch-Baumgartner 2000). It is one o f the most common variants reported in patients with this disorder. This variant has also been identified in 0.7% (342/50488) of European chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1386591 67), which is consistent with the carrier frequency for SLO. This variant occur s in the invariant region (+/- 1,2) of the splice consensus sequence and is pred icted to cause altered splicing leading to an abnormal or absent protein. Loss o f function of the DHCR7 gene is an established disease mechanism in individuals with SLO. In summary, this variant meets our criteria to be classified as pathog enic for SLO in an autosomal recessive manner based upon its segregation in affe cted individuals and predicted impact on protein function.

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