ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.1054C>T (p.Arg352Trp) (rs80338860)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000259783 SCV000329335 pathogenic not provided 2016-09-14 criteria provided, single submitter clinical testing Expression studies found that the R352W variant is associated with a greater than 90% decrease in expression of the DHCR7 protein (Fitzky et al., 1998).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000259783 SCV000700668 pathogenic not provided 2017-01-19 criteria provided, single submitter clinical testing
Invitae RCV000007189 SCV000824064 pathogenic Smith-Lemli-Opitz syndrome 2020-01-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 352 of the DHCR7 protein (p.Arg352Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs80338860, ExAC 0.006%). This variant has been reported as homozygous, or in combination with another DHCR7 variant, in multiple individuals affected with Smith-Lemli-Opitz syndrome (PMID: 15521979, 9653161, 18006960, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 6787). This variant has been reported to affect DHCR7 protein function (PMID: 9653161). A different missense substitution at this codon (p.Arg352Gln) has been determined to be pathogenic (PMID: 21696385, 16044199, 17441222). 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 RCV000007189 SCV000893240 pathogenic Smith-Lemli-Opitz syndrome 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000007189 SCV000917278 pathogenic Smith-Lemli-Opitz syndrome 2018-12-10 criteria provided, single submitter clinical testing Variant summary: DHCR7 c.1054C>T (p.Arg352Trp) 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 1.8e-05 in 275158 control chromosomes (gnomAD). The variant, c.1054C>T, has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (Fitzky_1998, Witsch-Baumgartner_2001, Waterham_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence showing more than 90% reduction in protein expression associated with this variant (Fitzky_1998). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000007189 SCV001163691 pathogenic Smith-Lemli-Opitz syndrome criteria provided, single submitter clinical testing
OMIM RCV000007189 SCV000027385 pathogenic Smith-Lemli-Opitz syndrome 2001-01-01 no assertion criteria provided literature only
GeneReviews RCV000007189 SCV000040845 pathologic Smith-Lemli-Opitz syndrome 2007-10-24 no assertion criteria provided curation Converted during submission to Pathogenic.
Counsyl RCV000007189 SCV000678001 pathogenic Smith-Lemli-Opitz syndrome 2015-06-14 no assertion criteria provided clinical testing

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