ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1090T>C (p.Cys364Arg)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238003 SCV000295212 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000238003 SCV000588552 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000238003 SCV000748049 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000775056 SCV000752428 pathogenic Familial hypercholesterolemia 2020-09-06 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 364 of the LDLR protein (p.Cys364Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with hypercholesterolemia (PMID: 1301956, 23375686, 26723464, 21722902, 25461735, 16314194, 10978268, 15556094). This variant is also known in the literature as Cys343Arg and FH Mexico-3. ClinVar contains an entry for this variant (Variation ID: 251657). This variant affects a cysteine residue located within an epidermal-growth-factor (EGF)–like domain 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: 3495735, 4750422). In addition, missense substitutions within the LDLR 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Several different missense substitution at this codon (p.Cys364Phe, p.Cys364Ser, p.Cys364Tyr) have been reported in individuals affected with hypercholesterolemia (PMID: 11196104, 21310417, 28379029). This suggests that the cysteine residue is critical for LDLR protein function. For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000775056 SCV000909156 pathogenic Familial hypercholesterolemia 2018-04-14 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This variant (also known as p.Cys343Arg in the mature protein and as FH Mexico-3 and FH Palermo-2) is a missense variant located in the EGF-like repeat B in the EGF precursor homology domain of the LDLR protein. This variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the EGF precursor homology domain (PMID: 3495735, 4750422). Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental studies with cells from a patient carrying both this variant and p.Cys352Tyr in trans showed 15-30% LDLR activity (PMID: 1301956). While this variant is rare in the general population (1/246160 chromosomes in the Genome Aggregation Database (gnomAD)), this variant has been reported in 10+ individuals affected with familial hypercholesterolemia (PMID: 1301956, 10978268, 15556094, 23064986, 25461735, 27940769). Based on available evidence, this variant is classified as Pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000238003 SCV001432590 pathogenic Familial hypercholesterolemia 1 2019-03-03 criteria provided, single submitter research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238003 SCV000606325 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786349 SCV000925132 pathogenic not provided 2017-06-09 no assertion criteria provided provider interpretation p.Cys364Arg (c.1090T>C) in exon 8 of the LDLR gene (NM_000527.4) Given the strong case data and its rarity in the general population, we consider this variant pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 16 unrelated cases of familial hypercholesterolemia (FH) (not including this patient's family). There is strong case data. This variant is present in ClinVar and is classified as likely pathogenic by one lab, LDLR-LOVD, British Heart Foundation Study. They have seen it in 3 individuals. This variant was found in 2 of 108 Mexican patients (Robles-Osorio et al 2005, Vaca et al 2011), 1 out of 642 Brazilian patients (Jannes et al 2015), 1 out of 60 patients from archived samples (Laurie and George 2009), 1 out of 526 Welsh patients (Haralambos et al 2012) and 7 of 725 unrelated Italian patients from 2 families (Bertolini et al 2000). A 7-year-old boy with severe FH (LDL in the 900s) had 2 copies of this variant. His parents were first cousins (Grego et al 2016). This variant is located in the EGF homology domain, which is important for ligand binding function (Davis et al, 1987). Ambry's internal structural analysis team predicts that this variant disrupts a cysteine-cysteine bridge known to be integral to structural stability of the domain. The cysteine at codon 364 is completely conserved across species, and neighboring amino acids are also highly conserved. Other variants have been reported in association with disease at this codon (p.Cys364Tyr, p.Cys364Ser) and nearby codons (p.Gln359Ter, p.Gln359_Asp360del, p.Asp362Alafx, p.Gln366Ter, p.Gln366Arg, p.Gln366Pro, p.Leu367Valfs, p.Cys368Arg, p.Cys368Ser, p.Cys368Tyr, p.Cys368Ter). The variant was reported online in 1 of 123,080 individuals in the Genome Aggregation Consortium Dataset (gnomAD;, which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 12,790 individuals of Latino descent (MAF=0.003%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).
Broad Institute Rare Disease Group, Broad Institute RCV000775056 SCV001422560 pathogenic Familial hypercholesterolemia 2020-01-22 no assertion criteria provided curation The p.Cys364Arg variant in LDLR has been reported in at least individuals with familial hypercholesterolemia, segregated with disease in 7 affected relatives from 2 families (PMID: 27940769, 23064986, 21722902, 1301956, 15556094, 11196104, 16314194, 21310417, 10978268, 25461735), and has been identified in 0.003% (1/34590) of Latino chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP {dbSNPrsNumber}). This variant has also been reported in ClinVar (Variation ID#: 251657). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies provide some evidence that the p.Cys364Arg variant may slightly impact protein function (PMID: 13019560). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual homozygous for this variant is highly specific for familial hypercholesterolemia based on the more severe phenotype and early onset of symptoms (PMID: 27940769). In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based on the number of affected probands with the variant and evidence of co-segregation with the disease.

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