Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Cambridge Genomics Laboratory, |
RCV005365205 | SCV007517022 | pathogenic | Familial hypercholesterolemia | 2024-08-19 | criteria provided, single submitter | clinical testing | The p.Glu140Ter variant is observed in 2/113.616 (0.0018%) alleles from individuals of gnomAD Non Finnish European background in gnomAD All. The p.Glu140Ter variant is novel (not in any individuals) in 1kG All. (PM2 - Moderate) | This variant is a stop gained variant which occurs in an exon of LDLR upstream of where nonsense mediated decay is predicted to occur. This variant has been previously classified as pathogenic, indicating that the region is critical to protein function. There are 736 downstream pathogenic loss of function variants, with the furthest variant being 722 residues downstream of this variant. This indicates that the region is critical to protein function. The p.Glu140Ter variant is a loss of function variant in the gene LDLR, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_000518.1:p.M1L and 842 others. (PVS1 - Very Strong) | The variant is observed in trans (in a compound heterozygous state) with another pathogenic variant. (PM3 - Moderate) |
| Labcorp Genetics |
RCV005365205 | SCV007375968 | pathogenic | Familial hypercholesterolemia | 2025-12-08 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Glu140*) 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 (rs748944640, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 1301956, 28965616, 30710474). This variant is also known as stop 119. ClinVar contains an entry for this variant (Variation ID: 251214). For these reasons, this variant has been classified as Pathogenic. |
| GENin |
RCV005365205 | SCV005921949 | pathogenic | Familial hypercholesterolemia | 2025-04-04 | criteria provided, single submitter | clinical testing | The c.418G>T p.(Glu140Ter) variant in LDLR is a nonsense variant predicted to create a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been seen in FH patients meeting clinical criteria (PS4_SUPPORTING; PMID 23375686). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001760 in European (non-Finnish) population, which is lower than the ClinGen FH VCEP threshold (<0.0002) so PM2_MODERATE is met. Based on the evidence listed above, we have classified this variant as Pathogenic. |
| Laboratory of molecular diagnosis of dyslipidemias, |
RCV000237501 | SCV001653591 | pathogenic | Hypercholesterolemia, familial, 1 | 2021-05-24 | criteria provided, single submitter | clinical testing | |
| Iberoamerican FH Network | RCV000237501 | SCV000748162 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
| LDLR- |
RCV000237501 | SCV000294699 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237501 | SCV000606112 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |