Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000238249 | SCV000295477 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003479080 | SCV004223789 | likely pathogenic | Familial hypercholesterolemia | 2023-11-14 | criteria provided, single submitter | clinical testing | Variant summary: LDLR c.1514G>A (p.Gly505Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251454 control chromosomes. c.1514G>A has been reported in the literature in individuals homozygous and heterozygous individuals affected with Familial Hypercholesterolemia (Lind_2002, Maglio_2014, Pavanello_2019). While both heterozygous and homozygous individuals displayed features including high cholesterol and cardiovascular disease, only some homozygotes had the full phenotype including Tendon xanthomas, leading authors to speculate the variant may result in a milder phenotype. Because of the presence of phenocopies in these patients with milder disease, this data cannot provide unequivocal conclusions about pathogenicity. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| All of Us Research Program, |
RCV000238249 | SCV005427609 | uncertain significance | Hypercholesterolemia, familial, 1 | 2024-03-24 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with aspartic acid at codon 505 of the LDLR protein. This variant is also known as p.Gly484Asp in the mature protein. This variant alters a conserved AA1 residue in the LDLR type B repeat 2 of the LDLR protein (a.a. 439-485), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least three unrelated individuals affected with familial hypercholesterolemia (PMID: 12052488, 24785115). It has been shown that this variant segregates with disease in four affected individuals across two families (PMID: 12052488, 24785115). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |