Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000003932 | SCV001960945 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2021-06-22 | reviewed by expert panel | curation | NM_000527.5(LDLR):c.2531G>A (p.Gly844Asp) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2 and is identified in 14 unrelated index cases fulfilling Simon-Broome criteria published in PMID: 7573037. PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PP3 - REVEL: 0,939. PP4 - Variant meets PM2 and is identified in 14 unrelated index cases fulfilling Simon-Broome criteria for FH published in PMID: 7573037. |
| LDLR- |
RCV000003932 | SCV000296027 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Color Diagnostics, |
RCV001523922 | SCV001733662 | pathogenic | Familial hypercholesterolemia | 2020-05-11 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Gly823Asp in the mature protein and as FH-Turku) replaces glycine with aspartic acid at codon 844 in the cytoplasmic domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the variant interferes with the basolateral sorting of LDLR with the effect that the protein was mis-targeted to the apical surface of the cell (PMID: 11389828). As a result, binding, internalization and degradation of LDL particles is significantly reduced (PMID: 7573037). Expression of the mutant protein failed to correct hypercholesterolemia in LDLR-deficient mice (PMID: 11389828). This variant has been reported in over ten unrelated individuals affected with familial hypercholesterolemia (PMID: 7573037). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. |
| Invitae | RCV001523922 | SCV004297888 | pathogenic | Familial hypercholesterolemia | 2023-09-12 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 11389828). 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: 3734). This variant is also known as p.Gly823Asp, FH-Turku. This missense change has been observed in individuals with autosomal dominant familial hypercholesterolemia (PMID: 7573037, 32522009, 33955087). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 844 of the LDLR protein (p.Gly844Asp). |
| OMIM | RCV000003932 | SCV000024097 | pathogenic | Hypercholesterolemia, familial, 1 | 2001-06-01 | no assertion criteria provided | literature only |