Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001373185 | SCV001569889 | likely pathogenic | Familial hypercholesterolemia | 2022-11-29 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 979168). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 32044282). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 654 of the LDLR protein (p.Leu654Pro). |
| Ambry Genetics | RCV002418863 | SCV002721448 | uncertain significance | Cardiovascular phenotype | 2018-10-11 | criteria provided, single submitter | clinical testing | The p.L654P variant (also known as c.1961T>C), located in coding exon 13 of the LDLR gene, results from a T to C substitution at nucleotide position 1961. The leucine at codon 654 is replaced by proline, an amino acid with similar properties. Another variant affecting this codon (p.L654F, c.1960C>T) was detected in a familial hypercholesterolemia cohort study; however, clinical details were not provided (Medeiros AM et al. Genet. Med., 2016 Apr;18:316-24). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| GBinsight Genetic Testing by GB Health |
RCV001258321 | SCV001312233 | likely pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | clinical testing | This variant, Leu654Pro, is predicted to be damaging to the LDL receptor protein by nearly all in silico algorithms. It is evolutionarily conserved. This variant was detected in a proband with heterozygous familial hypercholesterolemia. A single publication, by Setia et al. 2020) has identified this variant in (PMID: 32044282) in a family with familial hypercholesterolemia and this variant segregates with disease. |