ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1846-10G>T (rs368243304)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237306 SCV000295704 likely benign Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000237306 SCV000484791 uncertain significance Familial hypercholesterolemia 1 2019-08-22 criteria provided, single submitter clinical testing
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.
Invitae RCV000869000 SCV001010389 likely benign Familial hypercholesterolemia 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000869000 SCV001339284 likely benign Familial hypercholesterolemia 2017-07-06 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000237306 SCV001422916 likely benign Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The c.1846-10G>T variant in LDLR has been reported in at least 1 individual with Familial Hypercholesterolemia in ClinVar (Variation ID: 252072), and has been identified in 0.004595% (13/282890) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368243304). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely benign and likely pathogenic in ClinVar (Variation ID: 252072). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BP4, BP7 (Richards 2015).

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