ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1846-10G>T (rs368243304)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000599958 SCV000722314 likely benign not specified 2017-08-29 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000599958 SCV000919574 uncertain significance not specified 2017-11-14 criteria provided, single submitter clinical testing Variant summary: The LDLR c.1846-10G>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. In Alamut 3/5 splice prediction tools predict significant enhancement effect on the exon 13 acceptor site. In a published study also a slight increase in affinity was predicted for the splicing acceptor site using a different set of in silico tools (Usifo 2012). ESE finder predicts that this variant may affect the binding sites of the splicing factors SRp55, ASF/SF2 and SC35. Another study, using other in silico algorithms for splicing analyses, predicted also a deleterious score for the variant (Wang 2016). These predictions however have not been confirmed by functional studies. This variant was found in 12/277244 control chromosomes at a frequency of 0.0000433, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). The variant of interest has been reported in affected individuals (Usifo 2012, Wang 2016), where one of the patients also carried a pathogenic APOB variant c.10580G>A (p.Arg3527Gln), suggesting a possibly non-pathogenic role of variant of interest. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
LDLR-LOVD, British Heart Foundation RCV000237306 SCV000295704 likely benign Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000237306 SCV000484791 uncertain significance Familial hypercholesterolemia 2019-08-22 criteria provided, single submitter clinical testing

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