ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.906C>G (p.Phe302Leu) (rs80338858)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000020440 SCV000754771 pathogenic Smith-Lemli-Opitz syndrome 2019-08-29 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 302 of the DHCR7 protein (p.Phe302Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs80338858, ExAC 0.009%). This variant has been reported as in combination with another DHCR7 variant in several individuals affected with Smith-Lemli-Opitz syndrome, or SLOS (PMID: 10814720, 14981719, 12818773, 22226660, Invitae). ClinVar contains an entry for this variant (Variation ID: 21277). Experimental studies have shown that this missense change p.Phe302Leu has reduced enzyme activity in the cells of patients with SLOS (PMID: 15464432). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000020440 SCV001163697 pathogenic Smith-Lemli-Opitz syndrome criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000020440 SCV001193823 likely pathogenic Smith-Lemli-Opitz syndrome 2019-12-19 criteria provided, single submitter clinical testing NM_001360.2(DHCR7):c.906C>G(F302L) is classified as likely pathogenic in the context of Smith-Lemli-Opitz syndrome. Sources cited for classification include the following: PMID 14981719, 10814720, 15464432, 12818773 and 14981719. Classification of NM_001360.2(DHCR7):c.906C>G(F302L) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses and is very rare or not present in genetic databases of healthy individuals. Please note: this variant was assessed in the context of healthy population screening.
Integrated Genetics/Laboratory Corporation of America RCV000020440 SCV001338402 likely pathogenic Smith-Lemli-Opitz syndrome 2020-02-03 criteria provided, single submitter clinical testing Variant summary: DHCR7 c.906C>G (p.Phe302Leu) results in a non-conservative amino acid change located in the Loop 6-7 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251320 control chromosomes. c.906C>G has been reported in the literature as a compound heterozygous genotype in individuals affected with Smith-Lemli-Opitz Syndrome and has been reported as the third most common DHCR7 mutation in Spanish SLOS alleles (example, Yu_2000, Nowaczyk_2004, Ginat_2004, Witsch-Baumgartner_2005). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating a variant specific impact on protein function in a patient with a homozygous genotype has been reported. Two 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 (n=1)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneReviews RCV000020440 SCV000040855 pathologic Smith-Lemli-Opitz syndrome 2007-10-24 no assertion criteria provided curation Converted during submission to Pathogenic.

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