Total submissions: 13
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000211567 | SCV000294707 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Centre de Génétique Moléculaire et Chromosomique, |
RCV000211567 | SCV000503157 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subjects mutated among 2600 FH index cases screened = 7 , family members = 5 with co-segregation |
| Invitae | RCV002229196 | SCV000544658 | pathogenic | Familial hypercholesterolemia | 2023-07-17 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Cys143*) 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 present in population databases (rs199774121, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 9212177, 16542394, 21382890, 27831900). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys122*. ClinVar contains an entry for this variant (Variation ID: 226325). For these reasons, this variant has been classified as Pathogenic. |
| U4M - |
RCV000211567 | SCV000583677 | pathogenic | Hypercholesterolemia, familial, 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
| Fundacion Hipercolesterolemia Familiar | RCV000211567 | SCV000607456 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
| Department of Human Genetics, |
RCV000211567 | SCV000987026 | pathogenic | Hypercholesterolemia, familial, 1 | 2018-05-08 | criteria provided, single submitter | clinical testing | This nonsense mutation leads to a complete loss of the receptor function. In addition, the variant was observed in multiple studies in patients with FH. In our case the mutation was observed in a patient with TC up to 550 mg/dl at the age of 35. PMID: 9212177, 25487149 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001800540 | SCV002046188 | pathogenic | not provided | 2020-12-03 | criteria provided, single submitter | clinical testing | This nonsense variant causes the premature termination of LDLR protein synthesis. It has been reported in individuals affected with familial hypercholesteremia in the published literature (PMID: 9767373 (1998), 9452078 (1998), 27831900 (2016), 21382890 (2011), 19318025 (2009)). Therefore, the variant is classified as pathogenic. |
| Ambry Genetics | RCV002327075 | SCV002630846 | pathogenic | Cardiovascular phenotype | 2019-11-01 | criteria provided, single submitter | clinical testing | The p.C143* pathogenic mutation (also known as c.429C>A), located in coding exon 4 of the LDLR gene, results from a C to A substitution at nucleotide position 429. This changes the amino acid from a cysteine to a stop codon within coding exon 4. This alteration has been reported in multiple subjects with familial hypercholesterolemia (FH) (Descamps O et al. Clin. Genet., 1997 May;51:303-8; Lombardi P et al. Hum. Mutat., 1998;Suppl 1:S172-4; Amsellem S et al. Hum. Genet., 2002 Dec;111:501-10; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73). 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. |
| Institute for Clinical Genetics, |
RCV001800540 | SCV004026159 | pathogenic | not provided | 2022-09-08 | criteria provided, single submitter | clinical testing | PVS1, PS4, PP3 |
| Institute of Human Genetics, |
RCV000211567 | SCV004032280 | pathogenic | Hypercholesterolemia, familial, 1 | 2023-08-09 | criteria provided, single submitter | clinical testing | Criteria applied: PVS1,PS4,PM2_SUP |
| Cardiovascular Genetics Laboratory, |
RCV000211567 | SCV000268564 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-02-18 | no assertion criteria provided | clinical testing | |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000211567 | SCV000606117 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research | ||
| Clinical Genomics Program, |
RCV000211567 | SCV004100862 | pathogenic | Hypercholesterolemia, familial, 1 | 2020-12-31 | no assertion criteria provided | clinical testing | The p.Cys143* variant in the LDLR gene has been previously reported in at least 22 unrelated individuals with familial hypercholesterolemia (Descamps et al., 1997; Ekström et al., 1998; Lombardi et al., 1998; Jensen et al., 1999; Amsellem et al., 2002; van der Graaf et al., 2011; Natarajan et al., 2016), and one paper reported that it co-segregated with known or suspected FH in 71 relatives from 11 unrelated families (Descamps et al., 1997). This variant is also known as p.Cys122* in the literature. The p.Cys143* variant has been identified in 2/113,608 European (non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant leads to a premature stop codon in exon 4 of 18 coding exons, and is therefore predicted to undergo nonsensemediated decay resulting in a truncated or absent protein. Heterozygous loss of function is an established mechanism of disease for the LDLR gene. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Cys143* variant as pathogenic for autosomal dominant familial hypercholesterolemia based on the information above. [ACMG evidence codes used: PVS1; PS4; PM2] |