rs752596535
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.501C>A(p.Cys167*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000527.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.501C>A | p.Cys167* | stop_gained | Exon 4 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461652Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727122
GnomAD4 genome
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:12
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The c.501C>A (p.Cys167*) variant in the LDLR gene, that encodes for low density lipoprotein receptor, introduces a premature translation termination codon, resulting in an absent or disrupted protein product. The variant has been reported in several unrelated individuals (>10) affected with familial hypercholesterolemia (FH) (PMID: 10208479, 17539906, 21382890, 22698793, 26892515, 27680772, 34511120). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 33740630, 15321837, 20809525, 28645073). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 8828982, 22390909) and by several ClinVar submitters (ClinVar ID: 251274). This variant is found to be absent in the general population database, gnomAD and interpreted as pathogenic by multiple submitters in ClinVar (ClinVar ID: 200918). Therefore, the c.501C>A (p.Cys167*) variant in the LDLR gene is classified as pathogenic. -
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Familial hypercholesterolemia Pathogenic:6
The c.501C>A (p.Cys167*) variant in the LDLR gene, that encodes for low density lipoprotein receptor, introduces a premature translation termination codon, resulting in an absent or disrupted protein product. The variant has been reported in several unrelated individuals (>10) affected with familial hypercholesterolemia (FH) (PMID: 10208479, 17539906, 21382890, 22698793, 26892515, 27680772, 34511120). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 33740630, 15321837, 20809525, 28645073). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 8828982, 22390909) and by several ClinVar submitters (ClinVar ID: 251274). This variant is found to be absent in the general population database, gnomAD and interpreted as pathogenic by multiple submitters in ClinVar (ClinVar ID: 200918). Therefore, the c.501C>A (p.Cys167*) variant in the LDLR gene is classified as pathogenic. -
Variant summary: The LDLR c.501C>A (p.Cys167X) variant, alternatively also known as C146X, results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If NMD is escaped, this variant is expected truncate LDLR class A and B repeats, cysteine-rich domain, EGF-like calcium-binding domain, and EGF-like domain (InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory and others (e.g. p.Cys143X, p.Cys276X, p.Arg350X, etc.). This variant is absent in 121248 control chromosomes. In literature, this variant is reported as pathogenic variant and is found in many FH patients. The variant is particularly a frequent mutation in Dutch FH patients. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as Pathogenic. -
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This nonsense variant found in exon 4 of 18 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Loss-of-function variation in LDLR is an established mechanism of disease (PMID: 24404629). This is a known Pathogenic variant that has been previously reported as a heterozygous change in individuals with hypercholesterolemia (PMID: 7616128, 32041611, 34511120, 35913489). Functional studies indicate this variant may lead to reduced LDLR expression and low-density lipoprotein (LDL) uptake (PMID: 34511120). The c.501C>A (p.Cys167Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, c.501C>A (p.Cys167Ter) is classified as Pathogenic. -
This sequence change creates a premature translational stop signal (p.Cys167*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 7616128, 10208479, 12406975, 21382890, 22698793, 26892515, 27765764). 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. This variant is also known as Cys146X. ClinVar contains an entry for this variant (Variation ID: 200918). For these reasons, this variant has been classified as Pathogenic. -
This variant changes 1 nucleotide in exon 4 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 15 individuals affected with familial hypercholesterolemia (PMID: 7616128, 10208479, 17539906, 21382890, 22698793, 23833242, 26892515, 27765764). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
not provided Pathogenic:3
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Genetic testing: The patient had genetic testing for the familial LDLR mutation that was first identified in her brother, p.167*. at Ambry Genetics. Results reported on July 5, 2016 showed that the following variant was identified. Ambry classifies this variant as pathogenic. Given the loss of function nature of this variant and sufficient case data in other individuals we consider this variant pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant was previously identified in an affected family member of a patient. An individual with a missense variant at this codon is reported in Clinvar. Lombardi P et al. J. Lipid Res. 1995;36(4):860-7 reported this variant as it's other name (p.Cys146*) and Heath KE et al. Atherosclerosis 1999;143(1):41-54 reported this variant in a 27 Y male with FH. This variant is not reported in ExAC. -
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Homozygous familial hypercholesterolemia Pathogenic:1
The p.Cys167X variant in LDLR (also described as p.Cys146X in the literature) ha s been reported in the heterozygous state in >10 individuals with familial hyper cholesterolemia (FH), segregated with disease in one affected relative from one family (Lombardi 1995, Heath 1999, Fouchier 2001, Bodamer 2002, van der Graaf 20 11, Tichy 2012, Sharifi 2016) and was absent from large population studies. Addi tionally, this variant has been reported by other clinical laboratories in ClinV ar (Variation ID: 200918). This nonsense variant leads to a premature terminatio n codon at position 167, which is predicted to lead to a truncated or absent pro tein. Heterozygous loss of function of the LDLR gene is an established disease m echanism in FH. In summary, this variant meets our criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner bas ed upon predicted impact to the protein, presence in multiple affected individua ls and absence in the general population. ACMG/AMP Criteria applied (Richards 20 15): PVS1, PS4_Moderate, PM2. -
See cases Pathogenic:1
ACMG categories: PVS1,PM2,PP3,PP5 -
Cardiovascular phenotype Pathogenic:1
The p.C167* pathogenic mutation (also known as c.501C>A), located in coding exon 4 of the LDLR gene, results from a C to A substitution at nucleotide position 501. This changes the amino acid from a cysteine to a stop codon within coding exon 4. This mutation (referred to as p.C146X) has been described in multiple unrelated individuals with familial hypercholesterolemia (Lombardi P et al. J. Lipid Res. 1995;36(4):860-7; Heath KE et al. Atherosclerosis 1999;143(1):41-54; Rieck L et al. Clin Genet. 2020 11;98(5):457-467). In in vitro functional studies, this variant showed significantly reduced or absent protein expression and function compared to wild type (Hu H et al. Lipids Health Dis. 2021 Sep;20(1):101). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at