Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000237977 | SCV000295026 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Molecular Genetics Laboratory, |
RCV000237977 | SCV000540767 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular Medicine, |
RCV000826196 | SCV000967746 | pathogenic | Homozygous familial hypercholesterolemia | 2017-07-31 | criteria provided, single submitter | clinical testing | The p.Lys294SerfsX6 variant in LDLR (also described as p.Lys273SerfsX6 in the li terature) has been reported in at least 1 Czech individual with familial hyperch olesterolemia (FH; Kuhrova 2002, Tichy 2012). This variant has also been reporte d in ClinVar (Variation ID: 251499) and was absent from large population studies . It is predicted to cause a frameshift, which alters the protein?s amino acid s equence beginning at position 294 and leads to a premature termination codon 6 a mino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an establis hed disease mechanism in individuals with FH. In summary, the p.Lys294SerfsX6 va riant meets criteria to be classified as pathogenic for FH in an autosomal domin ant manner based upon the predicted impact to the protein and absence from the g eneral population. ACMG/AMP criteria applied: PVS1, PM2, PS4_Supporting. |
| Invitae | RCV001202718 | SCV001373842 | pathogenic | Familial hypercholesterolemia | 2022-01-11 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Lys294Serfs*6) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251499). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 11754108). This variant is not present in population databases (gnomAD no frequency). |
| Ambry Genetics | RCV002374398 | SCV002685198 | pathogenic | Cardiovascular phenotype | 2018-12-21 | criteria provided, single submitter | clinical testing | The c.881_882delAA pathogenic mutation, located in coding exon 6 of the LDLR gene, results from a deletion of two nucleotides at positions 881 to 882, causing a translational frameshift with a predicted alternate stop codon (p.K294Sfs*6). This mutation (also described as c.880_881delAA) was detected in a cohort of Czech patients with familial hypercholesterolemia (Kuhrová V et al. Hum. Mutat., 2001 Sep;18:253; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8). 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. |