ClinVar

Description

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.