Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000211607 | SCV000294601 | pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Centre de Génétique Moléculaire et Chromosomique, |
RCV000211607 | SCV000503130 | pathogenic | Familial hypercholesterolemia 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subjects mutated among 2600 FH index cases screened = 2 , family members = 2 |
U4M - |
RCV000211607 | SCV000583653 | pathogenic | Familial hypercholesterolemia 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
Cardiovascular Research Group, |
RCV000211607 | SCV000599324 | pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | curation | |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV000211607 | SCV000987703 | pathogenic | Familial hypercholesterolemia 1 | criteria provided, single submitter | clinical testing | ||
Cardiovascular Genetics Laboratory, |
RCV000211607 | SCV000268553 | pathogenic | Familial hypercholesterolemia 1 | 2008-07-09 | no assertion criteria provided | clinical testing | |
Broad Institute Rare Disease Group, |
RCV001249011 | SCV001422858 | likely pathogenic | Familial hypercholesterolemia | 2020-01-22 | no assertion criteria provided | curation | The c.313_313+1delCG variant in LDLR has been reported in 1 Australian and 1 French individual with familial hypercholesterolemia (PMID: 22883975, 1301956), and was absent from large population studies. This variant has also been reported in ClinVar as pathogenic (Variation ID: 226316). In vitro functional studies provide some evidence that the c.313_313+1delCG variant may slightly impact protein function (PMID: 1301956). However, these types of assays may not accurately represent biological function. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence, deletes the last base of the exon inducing a frameshift, and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia. There is an in-frame cryptic splice site within 6 basepairs of the intron-exon boundary that could result in a rescued transcript and may maintain function of LDLR. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_supporting, PS4_supporting, PVS1_moderate, PM2 (Richards 2015). |