rs879254787
Variant summary
Our verdict is Likely pathogenic. Variant got 11 ACMG points: 11P and 0B. PP1_ModeratePM2PM1PM3PS4_SupportingPP3PP4
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1090T>C (p.Cys364Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PM3, PP1_Moderate, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2025. The supporting evidence is as follows: PM1: Variant meets PM2 and alters Cys364, one of the highly conserved cysteine residues listed. PM2: PopMax MAF=0.00001666 (0.001666%) in Admixed American exomes + genomes (gnomAD v4.1.0). PP3: REVEL=0.984. PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 unrelated index cases (1 case with DLCN score >=6 from Research Lab of Molecular Genetics of Lipid Metabolism, Italy; 1 case with modified Simon-Broome criteria from PMID 23064986 (Ahmad et al., 2012), USA). PP1_Moderate: Variant segregates with FH phenotype in 5 informative meiosis from 2 families from different labs (Laboratory of Genetics and Molecular Cardiology, Brazil and Research Lab of Molecular Genetics of Lipid Metabolism, Italy): 3 affected family members have the variant and 2 unaffected family members do not have the variant.PM3: Variant meets PM2 and is identified in at least 1 clinically diagnosed HoFH, homozygous for the variant (PMID 37119068; PMID 27940769). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585298/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.1090T>C | p.Cys364Arg | missense_variant | Exon 8 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251338Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135882
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461436Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727054
GnomAD4 genome
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:4Uncertain:2
- -
- -
This missense variant replaces cysteine with arginine at codon 364 in the EGF-like repeat B of the LDLR protein. This variant is also known as p.Cys343Arg in the mature protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental studies with cells from a patient carrying both this variant and p.Cys352Tyr in trans showed 15-30% LDLR activity (PMID: 1301956). This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 1301956, 10978268, 15556094, 23064986, 25461735, 31345425, 34037665). This variant has also been observed in homozygous state in two individuals affected with severe homozygous familial hypercholesterolemia (PMID: 27940769, 37119068). It has been shown that this variant segregates with disease in multiple affected individuals across two families (PMID: 10978268). This variant has been identified in 1/251338 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Cys364Tyr, is considered to be disease-causing (ClinVar variation ID: 369852), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -
- -
- -
- -
Familial hypercholesterolemia Pathogenic:5
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 364 of the LDLR protein (p.Cys364Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301956, 10978268, 15556094, 16314194, 21722902, 23375686, 25461735, 26723464). 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: 251657). 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 disrupts the p.Cys343 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11196104, 21310417, 28379029), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Variant summary: LDLR c.1090T>C (p.Cys364Arg) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251538 control chromosomes. c.1090T>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (example, Hobbs_1992, Bertolini_2000, Laurie_2004, Cefalu_2001). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
- -
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, http://gnomad.broadinstitute.org; 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. -
This missense variant replaces cysteine with arginine at codon 364 in the EGF-like repeat B of the LDLR protein. This variant is also known as p.Cys343Arg in the mature protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental studies with cells from a patient carrying both this variant and p.Cys352Tyr in trans showed 15-30% LDLR activity (PMID: 1301956). This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 1301956, 10978268, 15556094, 23064986, 25461735, 31345425, 34037665). This variant has also been observed in homozygous state in two individuals affected with severe homozygous familial hypercholesterolemia (PMID: 27940769, 37119068). It has been shown that this variant segregates with disease in multiple affected individuals across two families (PMID: 10978268). This variant has been identified in 1/251338 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Cys364Tyr, is considered to be disease-causing (ClinVar variation ID: 369852), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -
not provided Pathogenic:2
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; http://gnomad.broadinstitute.org/), 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). -
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(C343R) and FH Mexico-3; This variant is associated with the following publications: (PMID: 29874871, 1301956, 27940769, 21722902, 26723464, 10978268, 25461735, 16314194, 15556094, 19446849, 23064986, 31345425, 23375686, 34037665, 32977124, 35339733, 2988123, 12459547) -
Cardiovascular phenotype Pathogenic:1
The p.C364R pathogenic mutation (also known as c.1090T>C), located in coding exon 8 of the LDLR gene, results from a T to C substitution at nucleotide position 1090. The cysteine at codon 364 is replaced by arginine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This particular alteration has been detected in conjunction with another alteration in the LDLR gene in an individual whose protein activity was 15-30% of normal (Hobbs HH et al. Hum Mutat. 1992;1(6):445-66), and subsequent studies have reported this alteration in several individuals diagnosed with FH (Bertolini S et al. Arterioscler Thromb Vasc Biol. 2000;20(9):E41-52). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the EGF-like 2 domain (Ambry internal data). In addition, alterations affecting the same amino acid position, p.C364F (c.1091G>T) and p.C364S (c.1091G>C), also have been described in patients with FH (Weiss N et al. J Inherit Metab Dis. 2000;23(8):778-90; Tichý L et al. Atherosclerosis. 2012;223(2):401-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at