Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000237554 | SCV000295842 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Centre de Génétique Moléculaire et Chromosomique, |
RCV000237554 | SCV000503453 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH (linked to ethnicity ?)/software prediction damaging |
Invitae | RCV001057854 | SCV001222369 | likely pathogenic | Familial hypercholesterolemia | 2024-01-08 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 684 of the LDLR protein (p.Ala684Thr). This variant is present in population databases (rs774730452, gnomAD 0.02%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 11005141; Invitae). This variant is also known as A663T. ClinVar contains an entry for this variant (Variation ID: 252192). 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) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Color Diagnostics, |
RCV001057854 | SCV001347392 | uncertain significance | Familial hypercholesterolemia | 2023-03-22 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Ala663Thr in the mature protein) replaces alanine with threonine at codon 684 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 11005141, 26608663). This variant has been identified in 4/251258 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237554 | SCV000606586 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research | ||
Natera, |
RCV001057854 | SCV002086861 | uncertain significance | Familial hypercholesterolemia | 2020-02-10 | no assertion criteria provided | clinical testing |