Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000508971 | SCV004022453 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2023-04-28 | reviewed by expert panel | curation | The variant NM_000527.5(LDLR):c.1067A>T (p.Asp356Val) is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP3, PS4_Supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PP3 - REVEL = 0.903 PS4_Supporting: Variant meets PM2, and is identified in 2 unrelated cases: 1 case with DLCN>6 from PMID: 30745730; 1 case with Simon-Broome criteria of possible FH from Color Health. So, PS4_Supporting is met. PP4 - Variant meets PM2 and is identified in at least 1 index case meeting clinical diagnostic criteria for FH, after alternative causes of high cholesterol were excluded. PM5 - 4 other missense variants in the same codon: 1) NM_000527.5(LDLR):c.1066G>T (p.Asp356Tyr) (ClinVar ID 226345) - Pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1066G>C (p.Asp356His) (ClinVar ID 251644) - Likely Pathogenic by these guidelines. 3) NM_000527.5(LDLR):c.1066G>A (p.Asp356Asn) (ClinVar ID 251643) - Unknown Significance by these guidelines. 4) NM_000527.5(LDLR):c.1067A>C (p.Asp356Ala) (ClinVar ID 251645) - Likely Pathogenic by these guidelines. There is 1 variant (p.Asp356Tyr) in the same codon classified as Pathogenic by these guidelines. So PM5 is met. |
| Color Diagnostics, |
RCV001187845 | SCV001354737 | likely pathogenic | Familial hypercholesterolemia | 2022-06-17 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Asp335Val in the mature protein) is located in the EGF-like repeat B of the EGF precursor homology 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). To our knowledge, functional studies have not been reported for this variant. To our knowledge, functional assays have not been performed for this variant. This variant has been observed in two unrelated individuals affected with familial hypercholesterolemia (PMID: 30745730, 34011801, Color Health internal data). One of the probands was an 11-year-old child and the mother was also an affected carrier (PMID: 30745730, 34011801). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Three, rare missense variants occurring at the same codon (p.Asp356His, p.Asp356Tyr, p.Asp356Ala) have been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 9104431, 11851376, 15256764, 19319977, 20145306, 20809525), suggesting that p.Asp356 residue is important for the LDLR protein function. Based on available evidence, this variant is classified as Likely Pathogenic. |
| Labcorp Genetics |
RCV001187845 | SCV001385849 | pathogenic | Familial hypercholesterolemia | 2024-02-08 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 356 of the LDLR protein (p.Asp356Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 30745730, 34011801, 34037665; Invitae). ClinVar contains an entry for this variant (Variation ID: 440623). 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 with a positive predictive value of 95%. This variant disrupts the p.Asp356 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9104431, 15998910). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000508971 | SCV000606317 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |