ClinVar Miner

Submissions for variant NM_001360.3(DHCR7):c.506C>T (p.Ser169Leu)

gnomAD frequency: 0.00001  dbSNP: rs80338855
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000020437 SCV000883711 pathogenic Smith-Lemli-Opitz syndrome 2020-02-03 criteria provided, single submitter clinical testing The DHCR7 c.506C>T, p.Ser169Leu variant (rs80338855) has been reported in multiple patients diagnosed with Smith-Lemli-Opitz syndrome (Correa-Cerro 2005, Witsch-Baumgartner 2000), and found with another pathogenic variant in one individual (Yu 2000). It is listed in ClinVar (Variation ID: 21274), and is observed in the general population databases at a frequency of 0.008 percent in the Exome Variant Server (1/12988 alleles), and 0.005 percent in the Genome Aggregation Database (12/245720 alleles). Based on the high frequency of this variant in published reports of Smith-Lemli-Opitz syndrome, the p.Ser169Leu variant is classified as pathogenic. References: Correa-Cerro L et al. 3beta-hydroxysterol Delta7-reductase and the Smith-Lemli-Opitz syndrome. Mol Genet Metab. 2005; 84(2):112-26. 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. Yu H et al. Spectrum of Delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome. Hum Mol Genet. 2000; 9(9):1385-91.
Illumina Laboratory Services,Illumina RCV000020437 SCV000915552 uncertain significance Smith-Lemli-Opitz syndrome 2017-11-26 criteria provided, single submitter clinical testing The DHCR7 c.506C>T (p.Ser169Leu) missense variant has been reported in at least three studies in which it is found in a total of four individuals with Smith-Lemli-Opitz syndrome (SLOS) in a compound heterozygous state and in nine out of 1,037 disease-associated alleles, none of which were homozygotes, however further details of zygosity are not given (Bianconi et al. 2011; Sparks et al. 2014; Boland et al. 2016; Eroglu et al. (2017). The second variant in the compound heterozygotes was not stated in two of the individuals, was an intron variant in one individual with a mild phenotype and normal IQ and a splice region/intron variant in the fourth individual. The p.Ser169Leu variant is described as one of the 12 most frequent disease-causing variants found at a frequency of 1.7% in patients with SLOS (a total of 10 alleles) (Correa-Cerro et al. 2005; Nowaczyk et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00012 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Ser169Leu variant is classified as a variant of unknown significance but suspicious for pathogenicity for Smith-Lemli-Opitz syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics RCV000020437 SCV001163333 pathogenic Smith-Lemli-Opitz syndrome criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000020437 SCV001194041 likely pathogenic Smith-Lemli-Opitz syndrome 2019-12-09 criteria provided, single submitter clinical testing NM_001360.2(DHCR7):c.506C>T(S169L) is classified as likely pathogenic in the context of Smith-Lemli-Opitz syndrome. Sources cited for classification include the following: PMID 15464432, 10814720, 22226660, 22391996, 21990131 and 10677299. Classification of NM_001360.2(DHCR7):c.506C>T(S169L) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020437 SCV001372248 pathogenic Smith-Lemli-Opitz syndrome 2020-06-14 criteria provided, single submitter clinical testing Variant summary: DHCR7 c.506C>T (p.Ser169Leu) results in a non-conservative amino acid change located in the Transmembrane domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250928 control chromosomes. c.506C>T has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (example, Yu_2000, Witsch-Baumgartner_2000, Bianconi_2011, Roullet_2012, Quelin_2012, Eroglu_2017). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect due to the compound heterozygous genotype of the cell line evaluated (Ginat_2004). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=1; Likely pathogenic, n=2; VUS, n=1). Some submitters have cited overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000020437 SCV001378784 pathogenic Smith-Lemli-Opitz syndrome 2021-11-09 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 169 of the DHCR7 protein (p.Ser169Leu). This variant is present in population databases (rs80338855, gnomAD 0.008%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10814720, 15896653, 21990131, 22226660, 22391996). ClinVar contains an entry for this variant (Variation ID: 21274). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DHCR7 protein function. For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory,University of Chicago RCV001818169 SCV002064488 likely pathogenic not provided 2017-10-31 criteria provided, single submitter clinical testing
GeneReviews RCV000020437 SCV000040851 not provided Smith-Lemli-Opitz syndrome no assertion provided literature only
Natera, Inc. RCV000020437 SCV002093043 pathogenic Smith-Lemli-Opitz syndrome 2021-03-19 no assertion criteria provided clinical testing

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