Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000237978 | SCV000295665 | likely benign | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Laboratory of Genetics and Molecular Cardiology, |
RCV000237978 | SCV000588608 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
Iberoamerican FH Network | RCV000237978 | SCV000748154 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
Mendelics | RCV000237978 | SCV002516656 | pathogenic | Hypercholesterolemia, familial, 1 | 2022-05-04 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002411091 | SCV002717317 | uncertain significance | Cardiovascular phenotype | 2017-10-23 | criteria provided, single submitter | clinical testing | The p.D601H variant (also known as c.1801G>C), located in coding exon 12 of the LDLR gene, results from a G to C substitution at nucleotide position 1801. The aspartic acid at codon 601 is replaced by histidine, an amino acid with similar properties, and is located in the LDL-receptor class B repeat 5. This alteration (with legacy nomenclature p.D680H) has been reported in 2 Brazilian familial hypercholesterolemia cohorts; however, clinical details were limited (Salazar LA et al. Hum. Mutat. 2002;19:462-3; Jannes CE et al. Atherosclerosis. 2015;238:101-7). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Invitae | RCV002518489 | SCV003520106 | pathogenic | Familial hypercholesterolemia | 2023-02-27 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 601 of the LDLR protein (p.Asp601His). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11933210, 25461735, 33231818). ClinVar contains an entry for this variant (Variation ID: 252038). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LDLR protein function. This variant disrupts the p.Asp601 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |