ClinVar Miner

Submissions for variant NM_001360.3(DHCR7):c.438T>G (p.Asn146Lys)

dbSNP: rs949177
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000779078 SCV000915554 uncertain significance Smith-Lemli-Opitz syndrome 2018-08-30 criteria provided, single submitter clinical testing The DHCR7 c.438T>G (p.Asn146Lys) missense variant has been reported in two studies in which it is found in a compound heterozygous state with other well-known pathogenic null variants in two individuals with Smith-Lemli-Opitz Syndrome (SLOS) (Jezela-Stanek et al. 2010; Quélin et al. 2011). The p.Asn146Lys variant was absent from 200 control chromosomes and is reported at a frequency of 0.000018 in the European (non-Finnish) population of the Genome Aggregation Database, but this is based on two alleles only in a region of good coverage so is presumed to be rare. Based on the limited evidence, the p.Asn146Lys variant is considered to be of unknown significance but suspicious of pathogenicity for Smith-Lemli-Opitz syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000779078 SCV000958135 pathogenic Smith-Lemli-Opitz syndrome 2023-08-29 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 146 of the DHCR7 protein (p.Asn146Lys). This variant is present in population databases (rs949177, gnomAD 0.002%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 20556518, 22226660). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 632172). 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. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV003222128 SCV003918725 likely pathogenic not provided 2023-04-10 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29433144, 27401223, 22226660, 20556518, 23042628, 11241839)
Natera, Inc. RCV000779078 SCV002093053 likely pathogenic Smith-Lemli-Opitz syndrome 2018-05-11 no assertion criteria provided clinical testing

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