Total submissions: 13
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| 3billion | RCV000237913 | SCV005905225 | uncertain significance | Hypercholesterolemia, familial, 1 | 2023-08-14 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.90 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.97 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with LDLR related disorder (ClinVar ID: VCV000251567). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. |
| Lildballe Lab, |
RCV004772883 | SCV005200543 | uncertain significance | Hypercholesterolemia | 2024-03-01 | criteria provided, single submitter | research | PM1(sup), PM2(sup), PP3(sup) |
| All of Us Research Program, |
RCV000237913 | SCV004820238 | uncertain significance | Hypercholesterolemia, familial, 1 | 2024-04-10 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Glu296Lys in the mature protein) replaces glutamic acid with lysine at codon 317 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 individuals affected with familial hypercholesterolemia (PMID: 20145306, 33418990, 36499307; ClinVar SCV000583768.1 and SCV003807681.1). It has also been reported in individuals clinically unaffected with hypercholesterolemia (PMID: 32522009, 35910211). This variant has been identified in 15/282452 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. |
| Ambry Genetics | RCV004020956 | SCV004068085 | uncertain significance | Cardiovascular phenotype | 2023-12-27 | criteria provided, single submitter | clinical testing | The p.E317K variant (also known as c.949G>A), located in coding exon 7 of the LDLR gene, results from a G to A substitution at nucleotide position 949. The glutamic acid at codon 317 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in subjects with familial hypercholesterolemia (FH), but has also been reported in subjects in the general population (Chmara M et al. J Appl Genet, 2010;51:95-106; Leren TP et al. Atherosclerosis, 2021 Apr;322:61-66; (Lacaze P et al. Circ Genom Precis Med, 2020 Aug;13:e002938; Van Hout CV et al. Nature, 2020 Oct;586:749-756). This amino acid position is highly 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. |
| Laboratorio de Genetica e Diagnostico Molecular, |
RCV000237913 | SCV003807681 | uncertain significance | Hypercholesterolemia, familial, 1 | 2023-01-26 | criteria provided, single submitter | clinical testing | ACMG classification criteria: PS4 supporting, PM2 moderated, PP3 supporting |
| Ai |
RCV001699171 | SCV002503569 | uncertain significance | not provided | 2021-03-19 | criteria provided, single submitter | clinical testing | |
| Broad Center for Mendelian Genomics, |
RCV000237913 | SCV001422634 | uncertain significance | Hypercholesterolemia, familial, 1 | 2020-01-23 | criteria provided, single submitter | curation | The p.Glu317Lys variant in LDLR has been reported in at least 2 individuals (including 1 Polish and 1 Dutch individuals) with Familial Hypercholesterolemia (PMID: 20145306) and 2 individuals with probable Familial Hypercholesterolemia (Variation ID: 251567), and has been identified in 0.02940% (9/30610) of South Asian chromosomes and 0.004010% (1/24936) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs746834464). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. 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 has also been reported pathogenic and likely pathogenic in ClinVar (Variation ID: 251567). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region (a ligand binding repeat) as p.Glu317Lys have been reported in association with disease in ClinVar and the literature, suggesting that this variant is in a mutational hot spot with functional importance and supports pathogenicity (PMID: 20145306; Variation ID: 251566, 183103, 251570, 251572, 251571). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM1, PP3, PS4_Supporting (Richards 2015). |
| Color Diagnostics, |
RCV001176042 | SCV001339859 | uncertain significance | Familial hypercholesterolemia | 2023-04-27 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Glu296Lys in the mature protein) replaces glutamic acid with lysine at codon 317 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 individuals affected with familial hypercholesterolemia (PMID: 20145306, 33418990, 36499307; ClinVar SCV000583768.1 and SCV003807681.1). It has also been reported in individuals clinically unaffected with hypercholesterolemia (PMID: 32522009, 35910211). This variant has been identified in 15/282452 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. |
| U4M - |
RCV000237913 | SCV000583768 | pathogenic | Hypercholesterolemia, familial, 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
| LDLR- |
RCV000237913 | SCV000295106 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV001699171 | SCV001957243 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Clinical Genetics, |
RCV001699171 | SCV001918745 | likely pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237913 | SCV000606284 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |