Total submissions: 12
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000003924 | SCV000294768 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Centre de Génétique Moléculaire et Chromosomique, |
RCV000003924 | SCV000503175 | likely 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 /FH-Afrikaner-3 / Software predictions: Damaging |
U4M - |
RCV000003924 | SCV000583693 | pathogenic | Familial hypercholesterolemia 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
Robarts Research Institute, |
RCV000003924 | SCV000782949 | likely pathogenic | Familial hypercholesterolemia 1 | 2018-01-02 | criteria provided, single submitter | clinical testing | |
Color | RCV000775043 | SCV000909140 | pathogenic | Familial hypercholesterolemia | 2018-08-13 | criteria provided, single submitter | clinical testing | Pathogenic variant based on current evidence: This missense variant (also known as p.Asp154Asn in the mature protein and as FH Afrikaner-3) is located in the fourth LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may impact the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental functional studies have shown that this variant causes significant defect in the LDLR activity (PMID: 7773731). This variant has been reported in numerous Afrikaner individuals affected with familial hypercholesterolemia and is thought to be a founder mutation in that population (PMID: 2799589, 9727745). This variant is rare in the general population and has been identified in 2/246152 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. |
Invitae | RCV000775043 | SCV000951227 | pathogenic | Familial hypercholesterolemia | 2018-11-19 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid with asparagine at codon 175 of the LDLR protein (p.Asp175Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with familial combined hyperlipidemia, familial hypercholesterolemia (FH) and has been shown to segregate with disease in FH families (PMID: 26342331, 2799589, 3430554, 2565980, 7773731, 24014831). This variant is also known as FH Afrikaner-3, FH3 and p.Asp154Asn in the literature. ClinVar contains an entry for this variant (Variation ID: 3726). Experimental studies have shown that this missense change causes a deleterious effect on LDL binding ability and reduced LDLR cell surface expression (PMID: 7773731). For these reasons, this variant has been classified as Pathogenic. |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV000003924 | SCV000987518 | pathogenic | Familial hypercholesterolemia 1 | criteria provided, single submitter | clinical testing | ||
Ce |
RCV001090451 | SCV001246004 | pathogenic | not provided | 2019-09-01 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000003924 | SCV000024089 | pathogenic | Familial hypercholesterolemia 1 | 1991-12-01 | no assertion criteria provided | literature only | |
Cardiovascular Genetics Laboratory, |
RCV000003924 | SCV000268568 | pathogenic | Familial hypercholesterolemia 1 | 2015-01-09 | no assertion criteria provided | clinical testing | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000003924 | SCV000606147 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | research | ||
Broad Institute Rare Disease Group, |
RCV000003924 | SCV001423090 | pathogenic | Familial hypercholesterolemia 1 | 2020-01-22 | no assertion criteria provided | curation | The p.Asp175Asn variant in LDLR has been reported in over 15 individuals with Familial Hypercholesterolemia, segregated with disease in 10 affected relatives from 2 families (PMID: 1757095,11845603, 2799589; DOI: 10.4172/2327-5790.1000167), and has been identified in 0.01088% (2/18386) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908033). 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 is a known founder variant in South Africa (PMID: 1757095). This variant has also been reported as a VUS, likely pathogenic variant, and pathogenic variant in ClinVar (Variation ID: 3726). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based on the number of affected probands with the varianht and the segregation of this variant with FH. ACMG/AMP Criteria applied: PS4, PP1_strong, PP3 (Richards 2015). |