ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.438T>G (p.Asn146Lys) (rs949177)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,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 likely pathogenic Smith-Lemli-Opitz syndrome 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 146 of the DHCR7 protein (p.Asn146Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs949177, ExAC 0.002%). This variant has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 20556518, 22226660). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. 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.

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