ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.1A>G (p.Met1Val) (rs104886033)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224026 SCV000280787 pathogenic not provided 2015-01-30 criteria provided, single submitter clinical testing
Counsyl RCV000169384 SCV000220774 likely pathogenic Smith-Lemli-Opitz syndrome 2014-10-07 criteria provided, single submitter literature only
GeneDx RCV000224026 SCV000568697 likely pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing The c.1A>G variant in the DHCR7 gene has been reported previously in two unrelated individuals with mild Smith-Lemli-Optiz syndrome when in trans with a splice site variant (Scalco et al., 2005; Witsch-Baumgartner et al., 2005). As this variant changes the translation initiator Methionine codon, the resultant protein is described as p.Met1?, using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine. In addition, a report has shown that protein initiation at Met59 of the DHCR7 gene does gives rise to a functional protein (Scalco et al., 2005). The c.1A>G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.1A>G variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000169384 SCV000923648 pathogenic Smith-Lemli-Opitz syndrome 2019-01-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169384 SCV000697854 likely pathogenic Smith-Lemli-Opitz syndrome 2017-07-20 criteria provided, single submitter clinical testing Variant summary: The DHCR7 c.1A>G (p.Met1Val) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/121390 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). This variant has been reported in multiple compound heterozygous SLOS patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. The variant of interest affects the translational start sight, however, Scalco_2005 indicates that translational initiation at Methionine 59 produces a functional protein. Therefore, suggesting that this would help explain the mild phenotype observed in affected individuals. Taken together, this variant is classified as likely pathogenic.
OMIM RCV000169384 SCV000027392 pathogenic Smith-Lemli-Opitz syndrome 2005-07-30 no assertion criteria provided literature only

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