Description
Variant summary: LDLR c.1876G>A (p.Glu626Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 253384 control chromosomes (gnomAD and Do_2015), predominantly at a frequency of 0.00062 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.00032 vs 0.0013), allowing no conclusion about variant significance. c.1876G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia and has been reported to segregate within disease, however it has also been reported in the compound heterozygous state in individuals with a pathogenic variant (e.g. Fouchier_2005, Medeiros_2014, Thormaehlen_2015, Benito-Vicente_2015, Do_2015, Grenkowitz_2016,Futema_2021, Graca_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least two publications report experimental evidence evaluating an impact on protein function, however the results indicate the effect is unclear (e.g. Thormaehlen_2015, Graca_2022). The variant was found to have normal expression and ligand binding levels, but showed reduced cellular internalization, approximately 60% of the WT protein, suggesting it may impact function (Graca_2022). Eleven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. The majority classified the variant as VUS (n=9), one classified it as likely pathogenic, and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
