Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV003229003 | SCV003926164 | likely pathogenic | not provided | 2022-10-28 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect with 50% reduction of LDL uptake and catabolism compared to wild type (Gomez et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31689621, Gomez2018[Article]) |
| Labcorp Genetics |
RCV003741244 | SCV004535400 | uncertain significance | Familial hypercholesterolemia | 2023-12-10 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 661 of the LDLR protein (p.Pro661Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 31689621). ClinVar contains an entry for this variant (Variation ID: 810849). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LDLR protein function. Experimental studies have shown that this missense change affects LDLR function (PMID: 31689621). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| All of Us Research Program, |
RCV001000104 | SCV005427634 | uncertain significance | Hypercholesterolemia, familial, 1 | 2024-03-24 | criteria provided, single submitter | clinical testing | This missense variant replaces proline with alanine at codon 661 of the LDLR protein. This variant is also known as p.Pro640Ala in the mature protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. An in vitro functional study using transfected heterologous cells has shown that this variant causes a 50-60% reduction in LDL uptake (PMID: 31689621). This variant has been reported in one individual affected with familial hypercholesterolemia (PMID: 31689621). 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. |
| Fundacion Favaloro, |
RCV001000104 | SCV001156525 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2019-05-29 | no assertion criteria provided | research |