ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1186+5G>C (rs879254821)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000417292 SCV000503310 pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1
GeneDx RCV000430561 SCV000535797 likely pathogenic not provided 2017-01-09 criteria provided, single submitter clinical testing Although the c.1186+5 G>C likely pathogenic variant in the LDLR gene has not been published previously, another variant affecting the same nucleotide (c.1186+5 G>A) has been reported in association with FH (Amsellem et al., 2002). Furthermore, the c.1186+5 G>C variant is predicted to destroy the canonical splice donor site in intron 8 and to cause abnormal gene splicing. Additionally, other splice site variants in the LDLR gene have been reported in the Human Gene Mutation Database in association with FH (Stenson et al., 2014). Moroever, the c.1186+5 G>C variant was not observed in the Exome Aggregation Consortium or in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Integrated Genetics/Laboratory Corporation of America RCV000770757 SCV000697186 uncertain significance not specified 2019-02-20 criteria provided, single submitter clinical testing Variant summary: LDLR c.1186+5G>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies (ACMG PP3). The variant allele was found at a frequency of 6.5e-05 in 30960 control chromosomes (gnomAD) indicating that this is a rare allele (ACMG PM2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1186+5G>C in individuals affected with Familial Hypercholesterolemia (FH) and no experimental evidence demonstrating its impact on protein function have been reported in the literature. However, another variant affecting the same nucleotide, c.1186+5G>A, has been predicted computationally to have similar splicing effect as the variant of interest and confirmed to generate an early stop codon after exon 8 by RT-PCR analysis while, it was functionally determined to affect LDLR expression, LDL binding, and LDL internalization. In addition, c.1186+5G>A was found in multiple FH patients (Etxebarria_2012, PMID 21990180; Amsellem_2002, PMID: 12436241). c.1186+5G>A has not yet been observed in our internal testing experience at the time of this classification. Three more neighboring splicing variants have been reported in the HGMD database as being associated with FH. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic (1x) and once as likely pathogenic. One of the submissions describes the detection of the variant in one FH subject. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic, until additional functional or clinical data become available.
Invitae RCV001039422 SCV001202952 uncertain significance Familial hypercholesterolemia 2019-10-21 criteria provided, single submitter clinical testing This sequence change falls in intron 8 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 375809). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000417292 SCV001432547 uncertain significance Familial hypercholesterolemia 1 2019-01-21 criteria provided, single submitter research

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