ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.440G>A (p.Gly147Asp) (rs777425801)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000421810 SCV000521158 likely pathogenic not provided 2016-09-28 criteria provided, single submitter clinical testing The G147D variant in the DHCR7 gene has been reported previously in individuals with clinical and/or biochemical features suggestive of Smith-Lemli-Optiz syndrome (Krakowiak et al., 2000; Witsch-Baumgartner et al, 2000). It has also been reported in two fetuses from the same family with holoprosencephaly who harbored the G147D variant in trans with a splice site pathogenic variant (Petracchi et al., 2011). The G147D variant was not observed in approximately 6500 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 G147D 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. The G147D variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Counsyl RCV000665794 SCV000789970 likely pathogenic Smith-Lemli-Opitz syndrome 2017-03-21 criteria provided, single submitter clinical testing
Invitae RCV000665794 SCV000946087 likely pathogenic Smith-Lemli-Opitz syndrome 2019-09-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 147 of the DHCR7 protein (p.Gly147Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs777425801, ExAC 0.01%). This variant has been observed in several individuals affected with Smith Lemli Opitz syndrome (PMID: 10995508, 12818773). ClinVar contains an entry for this variant (Variation ID: 381657). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics RCV000665794 SCV001163338 pathogenic Smith-Lemli-Opitz syndrome criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000665794 SCV001361500 pathogenic Smith-Lemli-Opitz syndrome 2019-02-04 criteria provided, single submitter clinical testing Variant summary: DHCR7 c.440G>A (p.Gly147Asp) 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 9e-05 in 243818 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (9e-05 vs 0.0043), allowing no conclusion about variant significance. c.440G>A has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (Krakowiak_2000, Petracchi_2011, Witsch-Baumgartner_2000, Goldenberg_2003). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submission from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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