Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000237544 | SCV000295157 | pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Centre de Génétique Moléculaire et Chromosomique, |
RCV000237544 | SCV000503285 | pathogenic | Familial hypercholesterolemia 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation |
Fundacion Hipercolesterolemia Familiar | RCV000237544 | SCV000607547 | uncertain significance | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Robarts Research Institute, |
RCV000237544 | SCV000782905 | pathogenic | Familial hypercholesterolemia 1 | 2018-01-02 | criteria provided, single submitter | clinical testing | |
Broad Institute Rare Disease Group, |
RCV000237544 | SCV001422911 | pathogenic | Familial hypercholesterolemia 1 | 2020-01-22 | no assertion criteria provided | curation | The p.Gln349Ter (sometimes called p.Gln328Ter) variant in LDLR has been reported in 3 individuals (including 1 Spanish individual) with Familial Hypercholesterolemia, segregated with disease in 2 affected relatives from 1 family in the literature and ClinVar (PMID: 11668640; Variation ID: 251611), and has been identified in 0.006064% (1/16490) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs748300548). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a dominant frequency for a disease with clinical variability/reduced penetrance. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported as a VUS and a pathogenic variant in ClinVar (Variation ID: 251611). This nonsense variant leads to a premature termination codon at position 349, 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. 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, PM2_Supporting, PS4_Supporting (Richards 2015). |