Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000485078 | SCV000568523 | pathogenic | not provided | 2017-02-21 | criteria provided, single submitter | clinical testing | The A480V pathogenic variant in the LDLR gene has been reported in the homozygous state in a Chinese male with disease manifestation at less than 10 years of age. The A480V variant segregated with disease in at least three heterozygous family members, all of whom demonstrated a milder phenotype (Lin et. al., 2008). The A480V variant has also been reported in two other patients with clinical signs of FH, including one proband with severe hypercholesterolemia at young age who was compound heterozygous for a W577G variant (Brusgaard et al., 2006; Jiang et al., 2016). The A480V variant resides within the LDL-receptor class B 2 repeat and results in a conservative amino acid substitution at a position that is highly conserved across species. In addition, functional analysis of homozygous LDLR expression demonstrated that, compared to normal controls, A480V LDLR expression, binding ability, and up-taking ability was 39%, 63%, and 76% respectively; heterozygous function was also shown to be impaired to a lesser degree (Lin et al., 2008). Finally, the A480V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). |
| Labcorp Genetics |
RCV001068840 | SCV001233973 | pathogenic | Familial hypercholesterolemia | 2019-11-28 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala480 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 26802169), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. This variant has been observed to segregate with familial hypercholesterolemia in a family (PMID: 18701038) and has been observed in individuals affected with this disease (PMID: 27830735, Invitae). This variant is also known as p.Ala459Val in the literature. ClinVar contains an entry for this variant (Variation ID: 420052). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 480 of the LDLR protein (p.Ala480Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. |