Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001857283 | SCV002313824 | pathogenic | Familial hypercholesterolemia | 2024-11-11 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 39 of the LDLR protein (p.Cys39Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 440543). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). For these reasons, this variant has been classified as Pathogenic. |
| ARUP Laboratories, |
RCV003736799 | SCV004563571 | uncertain significance | not provided | 2023-11-14 | criteria provided, single submitter | clinical testing | The LDLR c.115T>C; p.Cys39Arg variant (rs1555802275) is reported in the literature in an individual as part of a carrier screen (Grzymski 2020). This variant is reported in ClinVar (Variation ID: 440543) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.961). This variant is located at a highly conserved cysteine residue involved in disulfide bond formation critical for proper protein folding and stability (Daly 1995). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Daly NL et al. Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor. Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6334-8. PMID: 7603991. Grzymski JJ et al. Population genetic screening efficiently identifies carriers of autosomal dominant diseases. Nat Med. 2020 Aug;26(8):1235-1239. PMID: 32719484. |
| Ambry Genetics | RCV004023445 | SCV004897964 | uncertain significance | Cardiovascular phenotype | 2024-02-23 | criteria provided, single submitter | clinical testing | The c.115T>C (p.C39R) alteration is located in exon 2 (coding exon 2) of the LDLR gene. This alteration results from a T to C substitution at nucleotide position 115, causing the cysteine (C) at amino acid position 39 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000508808 | SCV000606018 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |