ClinVar Miner

Submissions for variant NM_002296.4(LBR):c.1639A>G (p.Asn547Asp) (rs587777171)

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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 RCV000087263 SCV000915398 likely pathogenic Greenberg dysplasia 2018-06-15 criteria provided, single submitter clinical testing The LBR c.1639A>G (p.Asn547Asp) missense variant has been reported two studies (Konstantinidou et al. 2008; Clayton et al. 2010). Konstantinidou et al. (2008) identified the variant in a homozygous state in an affected fetus born to consanguineous parents who were both shown to be carriers; a second affected fetus, although untested, was also presumed to be homozygous. Clayton et al. (2010) also identified the p.Asn547Asp variant in a heterozygous state in the consanguineous parents of an affected fetus who was not tested but was presumed to be homozygous. The p.Asn547Asp variant was absent from at least 500 control chromosomes and is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database, but this frequency is based on one allele in a region of good sequencing coverage. The variant is thus presumed to be rare. Functional studies showed that the p.ASn547Asp variant exhibited a considerable decrease in NADPH binding compared to wildtype in HeLa and LBR knockout cells as well as a nearly complete loss of de novo cholesterol synthesis in LBR knockout cell lines (Tsai et al. 2016; Turner and Schlieker 2016). Based on the collective evidence, the p.Asn547Asp variant is classified as likely pathogenic for Greenberg dysplasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000087263 SCV000120126 pathogenic Greenberg dysplasia 2010-07-01 no assertion criteria provided literature only

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