ClinVar Miner

Submissions for variant NM_001360.3(DHCR7):c.1336C>T (p.Arg446Trp)

gnomAD frequency: 0.00003  dbSNP: rs145043679
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000666265 SCV000790527 uncertain significance Smith-Lemli-Opitz syndrome 2017-03-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000666265 SCV002265694 likely pathogenic Smith-Lemli-Opitz syndrome 2024-04-15 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 446 of the DHCR7 protein (p.Arg446Trp). This variant is present in population databases (rs145043679, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with DHCR7-related conditions. ClinVar contains an entry for this variant (Variation ID: 551257). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DHCR7 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg446 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10677299, 12270273, 12818773, 27513191). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Ambry Genetics RCV002530674 SCV003739787 uncertain significance Inborn genetic diseases 2021-07-14 criteria provided, single submitter clinical testing Another likely pathogenic alteration (p.R446Q) has been reported at this amino acid position Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx RCV004588093 SCV005078996 likely pathogenic not provided 2023-12-03 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34426522, 23042628, zer2018[Abstract])

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