Description
Variant summary: LDLR c.940G>A (p.Gly314Arg) results in a non-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. As the variant affects the last conserved nucleotide of exon 6 adjacent to the intron 6 splice donor site, 4/4 computational tools predict a slight weakening of the canonical 5'-splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.8e-05 in 250802 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (4.8e-05 vs 0.0013), allowing no conclusion about variant significance. c.940G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (example, Widhalm_2007, Durst_2017, Futema_2017, Rimbert_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28104544, 28349888, 35047021, 17347910). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. 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 |
