ClinVar Miner

Submissions for variant NM_001360.3(DHCR7):c.724C>T (p.Arg242Cys) (rs80338856)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000389331 SCV000329334 pathogenic not provided 2017-05-26 criteria provided, single submitter clinical testing The R242C variant has been reported previously in association with SLOS (Krakowiak et al., 2000; Waterham et al., 2012; Tucci et al., 2016). This variant is located within membrane associated helix 5 (MAH 5) of the sterol sensing domain (Waterham et al., 2012). The R242C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R242C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret R242C as pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000389331 SCV000331535 pathogenic not provided 2015-09-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000020438 SCV000373917 pathogenic Smith-Lemli-Opitz syndrome 2017-04-27 criteria provided, single submitter clinical testing Across a selection of available literature, the DHCR7 c.724C>T (p.Arg242Cys) missense variant has been identified in a compound heterozygous state in at least six individuals with Smith-Lemli-Opitz syndrome and in two additional patients with unknown zygosity (Neklason et al. 1999; Krakowiak et al. 2000; Witsch-Baumgartner et al. 2000; Waye et al. 2005; Tucci et al. 2016). In a review, Boland et al. (2016) report that the p.Arg242Cys variant was found in 12 out of 1037 (1.2%) patient alleles across 30 studies. The p.Arg242Cys variant was absent from 50 controls and is reported at a frequency of 0.00029 in the African population of the Exome Aggregation. Functional studies demonstrated that the enzymatic activity in fibroblasts derived from a patient who was compound heterozygous for the p.Arg242Cys variant and another missense variant was significantly reduced (Ginat et al. 2004). Based on the evidence, the p.Arg242Cys variant is classified as pathogenic for Smith-Lemli-Opitz syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000020438 SCV000697848 pathogenic Smith-Lemli-Opitz syndrome 2016-08-04 criteria provided, single submitter clinical testing Variant summary: The DHCR7 c.724C>T (p.Arg242Cys) variant located in the transmembrane domain causes a missense change involving a conserved nucleotide with 5/5 in silico tools predicting a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 10/121036 (1/12106), which does not exceed the maximal expected allele frequency for a pathogenic DHCR7 variant of 1/230. The variant of interest has been reported in multiple affected individuals via publications. In addition, GeneReviews cites the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000020438 SCV000711726 likely pathogenic Smith-Lemli-Opitz syndrome 2015-09-11 criteria provided, single submitter clinical testing The p.Arg242Cys (NM_000060.2 c.724C>T) variant in DHCR7 has been reported in at least 6 individuals with clinical features of Smith-Lemli-Opitz syndrome who wer e compound heterozygotes for a second DHCR7 variant, and segregated with disease in one affected family member (Neklason 1999, Krakowiak 2000, Waye 2002, Correa -Cerro 2005, Waye 2005, Tucci 2016). This variant has also been identified in 19 /126,670 of European chromosomes by the Genome Aggregation Database (gnomAD, htt p://gnomad.broadinstitute.org; dbSNP rs80338856). Although this variant has been seen in the general population, its frequency is low enough to be consistent wi th a recessive carrier frequency. In vitro functional studies provide some evide nce that the p.Arg242Cys variant may impact protein function (Neklason 1999). In summary, although additional studies are required to fully establish its clinic al significance, the p.Arg242Cys variant is likely pathogenic for Smith-Lemli-Op itz syndrome in an autosomal recessive manner based on its occurrence in affecte d individuals, low frequency in controls, and functional data.
Invitae RCV000020438 SCV000825551 pathogenic Smith-Lemli-Opitz syndrome 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 242 of the DHCR7 protein (p.Arg242Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs80338856, ExAC 0.03%). This variant has been reported in several individuals affected with Smith-Lemli-Opitz syndrome (PMID: 10405455, 10677299, 10995508, 15464432, 15954111, 26969503). ClinVar contains an entry for this variant (Variation ID: 21275). Experimental studies have shown that this missense change results in a significant reduction of enzyme activity (PMID: 15464432). A different missense substitution at this codon (p.Arg242His) has been determined to be pathogenic (PMID: 10995508, 16044199, 11427181, 12818773, 15776424). This suggests that the arginine residue is critical for DHCR7 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000020438 SCV000893242 pathogenic Smith-Lemli-Opitz syndrome 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV000020438 SCV001163328 pathogenic Smith-Lemli-Opitz syndrome criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000020438 SCV001193935 likely pathogenic Smith-Lemli-Opitz syndrome 2019-12-04 criteria provided, single submitter clinical testing NM_001360.2(DHCR7):c.724C>T(R242C) is classified as likely pathogenic in the context of Smith-Lemli-Opitz syndrome. Sources cited for classification include the following: PMID 10677299, 15954111, 10995508, 18076100, 10405455, and 16983147. Classification of NM_001360.2(DHCR7):c.724C>T(R242C) 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.
GeneReviews RCV000020438 SCV000040852 pathologic Smith-Lemli-Opitz syndrome 2007-10-24 no assertion criteria provided curation Converted during submission to Pathogenic.
Myriad Women's Health, Inc. RCV000020438 SCV000678139 likely pathogenic Smith-Lemli-Opitz syndrome 2015-06-14 no assertion criteria provided clinical testing

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