ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.115T>C (p.Cys39Arg)

dbSNP: rs1555802275
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001857283 SCV002313824 uncertain significance Familial hypercholesterolemia 2021-05-03 criteria provided, single submitter clinical testing 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. 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). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of familial hypercholesterolemia (Invitae). ClinVar contains an entry for this variant (Variation ID: 440543). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 39 of the LDLR protein (p.Cys39Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine.
ARUP Laboratories, Molecular Genetics and Genomics, 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, Academisch Medisch Centrum RCV000508808 SCV000606018 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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