Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000238378 | SCV000294790 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Ambry Genetics | RCV002347937 | SCV002654126 | pathogenic | Cardiovascular phenotype | 2021-07-26 | criteria provided, single submitter | clinical testing | The c.557delG pathogenic mutation, located in coding exon 4 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 557, causing a translational frameshift with a predicted alternate stop codon (p.G186Vfs*20). This mutation has been previously reported in association with familial hypercholesterolemia (Guardamagna O et al. J Pediatr, 2009 Aug;155:199-204.e2). 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. |
| Labcorp Genetics |
RCV002518479 | SCV003442666 | pathogenic | Familial hypercholesterolemia | 2024-01-28 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gly186Valfs*20) 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 individual(s) with familial hypercholesterolemia (PMID: 8882879). This variant is also known as del165. ClinVar contains an entry for this variant (Variation ID: 251295). For these reasons, this variant has been classified as Pathogenic. |
| Laboratory for Molecular Medicine, |
RCV000238378 | SCV004848347 | pathogenic | Hypercholesterolemia, familial, 1 | 2020-03-10 | criteria provided, single submitter | clinical testing | The p.Gly186fsX20 variant in LDLR has been reported in at least 2 heterozygous individuals and one compound heterozygous individual with hypercholesterolemia (Reshef 1996, Ekström 1998, Guardamagna 2009). It was absent from large population studies, but has been reported in ClinVar (Variation ID 251295). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 186 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant hypercholesterolemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting. |
| Division of Human Genetics, |
RCV000238378 | SCV000536733 | pathogenic | Hypercholesterolemia, familial, 1 | 2015-08-20 | no assertion criteria provided | research |