Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000844754 | SCV000271389 | pathogenic | Homozygous familial hypercholesterolemia | 2019-06-07 | criteria provided, single submitter | clinical testing | The c.313+1G>C variant in LDLR has been identified in >80 Spanish individuals with familial hypercholesterolemia (FH; Tejedor 2011). It has also been identified in 1/113710 European chromosomes by gnomAD (https://gnomad.broadinstitute.org). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of LDLR function is an established disease mechanism in FH. In summary, this variant meets our criteria to be classified as pathogenic for FH in an autosomal dominant manner. PVS1_Strong, PS4, PM2. |
LDLR- |
RCV000213674 | SCV000294605 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Cardiovascular Research Group, |
RCV000213674 | SCV000322889 | pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | 0/208 non-FH alleles; 0/32 normolipidemic individuals; 0/60 healthy control individuals |
Centre de Génétique Moléculaire et Chromosomique, |
RCV000213674 | SCV000503134 | pathogenic | Familial hypercholesterolemia 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subject mutated among 2600 FH index cases screened = 1 |
Fundacion Hipercolesterolemia Familiar | RCV000213674 | SCV000607444 | pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000213674 | SCV000606075 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | research | ||
Iberoamerican FH Network | RCV000213674 | SCV000748173 | pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | no assertion criteria provided | research | |
Broad Institute Rare Disease Group, |
RCV001249083 | SCV001423040 | uncertain significance | Familial hypercholesterolemia | 2020-01-22 | no assertion criteria provided | curation | The c.313+1G>C variant in LDLR has been reported in at least 5 Spanish and/or Dutch individuals with familial hypercholesterolemia (PMID: 21935675, 7616128, 10790219), and has been identified in 0.0009% (1/113710) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs112029328). This variant has also been reported in ClinVar as both pathogenic and likely pathogenic (Variation ID: 228358). This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. 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. Heterozygous loss of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_moderate, PS4_supporting (Richards 2015). |