Total submissions: 9
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000238180 | SCV000295571 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Centre de Génétique Moléculaire et Chromosomique, |
RCV000238180 | SCV000503382 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subjects mutated among 2600 FH index cases screened = 9 , family member = 1 with co-segregation |
| U4M - |
RCV000238180 | SCV000583860 | pathogenic | Hypercholesterolemia, familial, 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
| Cardiovascular Research Group, |
RCV000238180 | SCV000599377 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | curation | |
| Robarts Research Institute, |
RCV000238180 | SCV000782921 | pathogenic | Hypercholesterolemia, familial, 1 | 2018-01-02 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV003391008 | SCV004110373 | pathogenic | LDLR-related disorder | 2023-03-21 | criteria provided, single submitter | clinical testing | The LDLR c.1681C>T variant is predicted to result in premature protein termination (p.Gln561*). This variant is also described using legacy nomenclature as p.Gln540*, has been reported in the heterozygous and homozygous states in individuals with hypercholesterolemia (Webb et al. 1996. PubMed ID: 9026534; Amsellem et al. 2002. PubMed ID: 12436241). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic. |
| Labcorp Genetics |
RCV003581630 | SCV004298369 | pathogenic | Familial hypercholesterolemia | 2024-12-18 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gln561*) 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 clinical features of LDLR-related conditions (PMID: 8292093, 32041611). This variant is also known as Gln540*. ClinVar contains an entry for this variant (Variation ID: 251965). For these reasons, this variant has been classified as Pathogenic. |
| Laboratory for Molecular Medicine, |
RCV004017562 | SCV004847697 | pathogenic | Homozygous familial hypercholesterolemia | 2019-04-12 | criteria provided, single submitter | clinical testing | The p.Gln561X variant in LDLR (also described as p.Gln440X in the literature) has been reported in >10 individuals with familial hypercholesterolemia (FH), including one homozygous individual where the variant segregated with disease in at least 4 affected family members (Feher 1993, Webb 1996, Amsellem 2002, Vandrovcova 2013, ClinVar submission accessions: SCV000503382.1, SCV000583860.1). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 561, which is predicted to lead to a truncated or absent protein. Additionally, in vitro functional studies support an impact on protein function (Webb 1996). Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant FH. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PVS1, PM2, PP1_Supporting, PS3_Supporting, PS4_Moderate. |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000238180 | SCV000606479 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |