ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.1210C>T (p.Arg404Cys) (rs61757582)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723830 SCV000700667 pathogenic not provided 2017-04-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000007190 SCV000893238 pathogenic Smith-Lemli-Opitz syndrome 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000007190 SCV000938503 pathogenic Smith-Lemli-Opitz syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 404 of the DHCR7 protein (p.Arg404Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs61757582, ExAC 0.01%). This variant has been reported in multiple individuals affected with Smith Lemli Opitz syndrome (PMID: 15896653, 9653161, 12818773, 10677299). ClinVar contains an entry for this variant (Variation ID: 6788). This variant has been reported to affect DHCR7 protein function (PMID: 9653161). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000007190 SCV001163686 pathogenic Smith-Lemli-Opitz syndrome criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000007190 SCV001193936 pathogenic Smith-Lemli-Opitz syndrome 2019-12-04 criteria provided, single submitter clinical testing NM_001360.2(DHCR7):c.1210C>T(R404C) is classified as pathogenic in the context of Smith-Lemli-Opitz syndrome and can be associated with mild to severe forms of this disease. Sources cited for classification include the following: PMID 10677299, 22438180, 15954111, and 22438180. Classification of NM_001360.2(DHCR7):c.1210C>T(R404C) is based on the following criteria: This is a well-established pathogenic variant in the literature that 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.
Integrated Genetics/Laboratory Corporation of America RCV000007190 SCV001361497 pathogenic Smith-Lemli-Opitz syndrome 2019-03-21 criteria provided, single submitter clinical testing Variant summary: DHCR7 c.1210C>T (p.Arg404Cys) results in a non-conservative amino acid change in 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 268406 control chromosomes (gnomAD). The variant of interest has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (Fitzky_1998, Witsch-Baumgartner_2000). These data indicate that the variant is very likely to be associated with disease. Both publications reported that expression of p.Arg404Cys in human cell line resulted in similar transcript but reduced protein expression as compared with wildtype (<10%, Fitzky_1998, Witsch-Baumgartner_2000). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000007190 SCV000027386 pathogenic Smith-Lemli-Opitz syndrome 2001-01-01 no assertion criteria provided literature only
GeneReviews RCV000007190 SCV000040846 pathologic Smith-Lemli-Opitz syndrome 2007-10-24 no assertion criteria provided curation Converted during submission to Pathogenic.

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