Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000791411 | SCV000285010 | pathogenic | Familial hypercholesterolemia | 2023-12-06 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Trp4*) 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 (rs756039188, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 7903864, 16314194, 20428891, 21376320, 21868016). ClinVar contains an entry for this variant (Variation ID: 237860). For these reasons, this variant has been classified as Pathogenic. |
LDLR- |
RCV000227275 | SCV000294414 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
U4M - |
RCV000227275 | SCV000583622 | pathogenic | Hypercholesterolemia, familial, 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | ACMG Guidelines: Pathogenic (i) |
Fundacion Hipercolesterolemia Familiar | RCV000227275 | SCV000607403 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
Iberoamerican FH Network | RCV000227275 | SCV000748035 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
Broad Center for Mendelian Genomics, |
RCV000227275 | SCV001422788 | pathogenic | Hypercholesterolemia, familial, 1 | 2020-01-22 | criteria provided, single submitter | curation | The p.Trp4Ter (sometimes called p.Trp-18Ter) variant in LDLR has been reported in 53 individuals (including including 48 Spanish, 3 Chinese, and 2 Mexican individuals) with Familial Hypercholesterolemia, segregated with disease in 3 affected relatives from 1 family (PMID: 7903864, 20428891, 21868016, 1301956, 16314194), and has been identified in 0.002897% (1/34516) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs756039188). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic in ClinVar (Variation ID: 237860). This nonsense variant leads to a premature termination codon at position 4, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in Familial Hypercholesterolemia. One pathogenic variant with the same amino acid change as this variant has been reported in association with Familial Hypercholesterolemia in ClinVar, supporting that this variant may be pathogenic (Variation ID: 250973). In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on the predicted impact of the variant and multiple occurrences in individuals with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PS1, PS4, PP1 (Richards 2015). |
Revvity Omics, |
RCV000227275 | SCV002017124 | pathogenic | Hypercholesterolemia, familial, 1 | 2019-07-29 | criteria provided, single submitter | clinical testing |