ClinVar Miner

Submissions for variant NM_001360.3(DHCR7):c.964-1G>C (rs138659167)

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Total submissions: 40
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000079661 SCV000233039 pathogenic not provided 2017-01-12 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000180570 SCV000247185 pathogenic Smith-Lemli-Opitz syndrome 2019-10-10 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
GeneDx RCV000079661 SCV000321549 pathogenic not provided 2019-12-06 criteria provided, single submitter clinical testing 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); RT-PCR analysis revealed IVS8-1 G>C led to the use of an alternative SAS upstream from the mutated intron 8 splice site with the insertion of intron sequence, a shift of the reading frame, and premature stop (Fitzky et al., 1998); This variant is associated with the following publications: (PMID: 23293579, 26685159, 9653161, 10995508, 21777499, 33578785, 33204589, 32058062, 31589614, 31980526, 32055014, 32304219, 31618753, 31974414, 32257592, 31395954, 30925529, 9634533, 30947698, 11857552, 11298379, 29455191, 30609409, 28805615, 25533962, 28369852, 28250423, 12949967, 27065010, 25108116, 17965227, 25405082, 20556518, 22975760)
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.
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.
Fulgent Genetics,Fulgent Genetics RCV000180570 SCV000611262 pathogenic Smith-Lemli-Opitz syndrome 2017-05-18 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000079661 SCV000613096 pathogenic not provided 2020-09-22 criteria provided, single submitter clinical testing This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org); however DHC7 c.964-1G>C is reported to account for 1/3rd of all pathogenic alleles and described as a founder variant (PMID:11175299,17965227,16906538). Assessment of experimental evidence suggests this variant results in abnormal protein function. RT-PCR study showed that disruption of this splice site led to a premature stop codon (PMID:9653161). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Invitae RCV000180570 SCV000630077 pathogenic Smith-Lemli-Opitz syndrome 2020-11-01 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 8 of the DHCR7 gene. RNA analysis indicates that this variant induces altered splicing and likely results in a truncated 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000180570 SCV000697859 pathogenic Smith-Lemli-Opitz syndrome 2016-01-21 criteria provided, single submitter clinical testing
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.
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
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000180570 SCV000743877 pathogenic Smith-Lemli-Opitz syndrome 2017-07-28 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000180570 SCV000745303 pathogenic Smith-Lemli-Opitz syndrome 2016-01-25 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
Ambry Genetics RCV000717414 SCV000848264 pathogenic History of neurodevelopmental disorder 2018-01-15 criteria provided, single submitter clinical testing The c.964-1G>C intronic pathogenic mutation (also known as IVS8-1G>C) results from a G to C substitution one nucleotide before coding exon 7 of the DHCR7 gene. This alteration is one of the most common DHCR7 mutations in North America and Western Europe, and was found to account for 35% of mutations in a cohort of 263 individuals with Smith-Lemli-Optiz syndrome (SLOS) (<span style="background-color:initial">Witsch-Baumgartner M et al. <span style="background-color:initial">J. Med. Genet. 2008 Apr;45(4):200-9)<span style="background-color:initial">. <span style="background-color:initial">This mutation was reported in the homozygous state in a fetus with holoprosencephaly and multiple congenital anomalies as well as in newborns with a severe phenotype (Nowaczyk MJ et al. Am J Med Genet<span style="background-color:initial">. 2001;103(1): 75-80). In one study, this mutation was also identified in the compound heterozygous state in two individuals with SLOS; analysis of cDNA isolated from fibroblasts of one individual demonstrated the use of an alternative splice acceptor site, leading to a transcript with a shift in reading frame and a premature stop codon (Fitzky BU et al. Proc Natl Acad Sci USA.<span style="background-color:initial"> 1998;95(14):8181-8186). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000180570 SCV000891754 pathogenic Smith-Lemli-Opitz syndrome 2018-06-22 criteria provided, single submitter research ACMG codes: PVS1, PS3, PM2, PP5
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000180570 SCV001157268 pathogenic Smith-Lemli-Opitz syndrome 2020-06-02 criteria provided, single submitter clinical testing The DHCR7 c.964-1G>C variant (rs138659167) is reported in the literature as the most common variant in individuals affected with Smith-Lemli-Opitz (SLO) syndrome (reviewed in Witsch-Baumgartner 2015), found in both the homozygous and compound heterozygous state (Fitzky 1998, Krakowiak 2000, Witsch-Baumgartner 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 93725), and is found in the general population with an overall allele frequency of 0.39% (1,010/262,084 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice acceptor site of intron 8, which is likely to disrupt gene function. Functional studies from patient mRNA show an insertion of 134 nucleotides between exons 8 and 9, leading to a premature termination codon (Fitzky 1998). Based on available information, the c.964-1G>C variant is considered to be pathogenic. References: Fitzky BU et al. Mutations in the Delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8181-6. Krakowiak PA et al. Mutation analysis and description of sixteen RSH/Smith-Lemli-Opitz syndrome patients: polymerase chain reaction-based assays to simplify genotyping. Am J Med Genet. 2000 94(3):214-27. Witsch-Baumgartner M et al. Mutational spectrum in the Delta7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome. Am J Hum Genet. 2000 66(2):402-12. Witsch-Baumgartner M and Lanthaler B. et al. Birthday of a syndrome: 50 years anniversary of Smith-Lemli-Opitz Syndrome. Eur J Hum Genet. 2015 Mar;23(3):277-8.
Baylor Genetics RCV000180570 SCV001163695 pathogenic Smith-Lemli-Opitz syndrome criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000180570 SCV001193925 pathogenic Smith-Lemli-Opitz syndrome 2019-11-12 criteria provided, single submitter clinical testing NM_001360.2(DHCR7):c.964-1G>C is classified as pathogenic in the context of Smith-Lemli-Opitz syndrome and is associated with the severe form of the disease. Sources cited for classification include the following: PMID 15952211 and 10677299. Classification of NM_001360.2(DHCR7):c.964-1G>C is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000079661 SCV001245961 pathogenic not provided 2021-05-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000180570 SCV001251430 pathogenic Smith-Lemli-Opitz syndrome 2019-10-18 criteria provided, single submitter clinical testing The variant was confirmed as compound heterozygous with a pathogenic variant (NM_001163817.1: c.452G>A).
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000180570 SCV001367096 pathogenic Smith-Lemli-Opitz syndrome 2018-09-26 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Johns Hopkins Genomics, Johns Hopkins University RCV000180570 SCV001425360 pathogenic Smith-Lemli-Opitz syndrome 2020-03-31 criteria provided, single submitter clinical testing DHCR7 c.964-1G>C is believed to be the most common disease-causing variant associated with Smith-Lemli-Opitz (SLO) syndrome and has been identified in affected individuals in both the homozygous and heterouzygous state. Five submitters in ClinVar classify this variant as either pathogenic or likely pathogenic. This DHCR7 variant (rs138659167) is present in a large population dataset (gnomAD: 1010/262084 total alleles; 0.3854%; no homozygotes) at a frequency that is consistent with the carrier frequency for SLO. We consider this variant to be pathogenic.
New York Genome Center RCV001263353 SCV001441395 pathogenic Global developmental delay 2020-02-06 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000079661 SCV001447515 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000079661 SCV001468075 pathogenic not provided 2020-08-25 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000180570 SCV001810398 pathogenic Smith-Lemli-Opitz syndrome 2021-07-22 criteria provided, single submitter 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
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000180570 SCV000733106 pathogenic Smith-Lemli-Opitz syndrome no assertion criteria provided clinical testing
Gharavi Laboratory,Columbia University RCV000079661 SCV000809236 pathogenic not provided 2018-09-16 no assertion criteria provided research
Hadassah Hebrew University Medical Center RCV000180570 SCV000998809 pathogenic Smith-Lemli-Opitz syndrome no assertion criteria provided clinical testing known pathogenic variant: PMID 28805615, 22226660, 28369852, 12818773, 12914579, 29455191, 22929031 and others.
GeneReviews RCV000180570 SCV000999075 pathogenic Smith-Lemli-Opitz syndrome 2019-10-02 no assertion criteria provided literature only
Reproductive Health Research and Development,BGI Genomics RCV000180570 SCV001142422 pathogenic Smith-Lemli-Opitz syndrome 2020-01-06 no assertion criteria provided curation NG_012655.2(NM_001360.2):c.964-1G>C in the DHCR7 gene has an allele frequency of 0.012 in Ashkenazi Jewish subpopulation in the gnomAD database. The c.964-1G>C (IVS8-1G>C) is the most common pathogenic variant for Smith-Lemli-Opitz syndrome accounting for at least 29% of all disease alleles (PMID: 24824134). Functional analysis of the variant using RT-PCR in patient with 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 (PMID: 9683613). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PS4; PS3.
GenomeConnect, ClinGen RCV000180570 SCV001423437 not provided Smith-Lemli-Opitz syndrome no assertion provided phenotyping only Variant interpretted as Pathogenic and reported on 06-04-2019 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000180570 SCV001469217 pathogenic Smith-Lemli-Opitz syndrome 2020-05-06 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000079661 SCV001550205 pathogenic not provided no assertion criteria provided clinical testing The DHCR7 c.964-1G>C variant has been reported in over 70 cases of autosomal recessive Smith Lemli Opitz syndrome (SLOS) and is the most common variant known to cause the disorder, accounting for ~28% of disease alleles (Nowaczyk_1998_PMID:20301322; Fitzky_1998_PMID:9653161; Krakowiak_2000_PMID:10995508; Witsch-Baumgartner_2001_PMID:11175299; DeBarber_2011_PMID:21777499). The variant was identified in dbSNP (ID: rs138659167) and ClinVar (classified as pathogenic by Laboratory for Molecular Medicine, Invitae and 21 other laboratories, and as likely pathogenic by Genetic Services Laboratory, University of Chicago and Equipe Genetique des Anomalies du Developpement, Université de Bourgogne). The variant was identified in control databases in 1010 of 262084 chromosomes (0 homozygous) at a frequency of 0.003854 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 116 of 9812 chromosomes (freq: 0.01182), European (non-Finnish) in 722 of 118782 chromosomes (freq: 0.006078), Other in 31 of 6836 chromosomes (freq: 0.004535), Latino in 67 of 34828 chromosomes (freq: 0.001924), African in 41 of 22690 chromosomes (freq: 0.001807), European (Finnish) in 30 of 19724 chromosomes (freq: 0.001521) and South Asian in 3 of 30116 chromosomes (freq: 0.0001), but was not observed in the East Asian population. The c.964-1G>C variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict the loss of the canonical 3' splice site. Functional analysis has confirmed this aberrant splicing prediction and has revealed the use of an alternative splice acceptor site that produces a shifted reading frame and premature stop codon (Fitzky_1998_PMID:965316). Another functional study suggests that the c.964-1G>C variant disrupts SMO cilia localization and SHH pathway activation due to reduced cholesterol biosynthesis and reduced levels of the DHCR7 transcript (Blassberg_2016_PMID:26685159). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000079661 SCV001799020 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000079661 SCV001806972 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000079661 SCV001955116 pathogenic not provided no assertion criteria provided clinical testing

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