Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV002486679 | SCV005375305 | uncertain significance | Hypercholesterolemia, familial, 1 | 2024-08-30 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.2440C>T (p.Arg814Trp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 30 August 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00002229 (0.002229%) in East Asian exomes (gnomAD v4.1.0). |
| Labcorp Genetics |
RCV002040636 | SCV002302993 | uncertain significance | Familial hypercholesterolemia | 2021-09-17 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with tryptophan at codon 814 of the LDLR protein (p.Arg814Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs746616623, ExAC 0.003%). This variant has been observed in individual(s) with myocardial infarction (PMID: 25487149). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV002458987 | SCV002737260 | uncertain significance | Cardiovascular phenotype | 2021-08-18 | criteria provided, single submitter | clinical testing | The p.R814W variant (also known as c.2440C>T), located in coding exon 17 of the LDLR gene, results from a C to T substitution at nucleotide position 2440. The arginine at codon 814 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in an early onset myocardial infarction cohort, being identified in a case and a control with limited clinical details (Do R et al. Nature, 2015 Feb;518:102-6). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV002486679 | SCV002781017 | uncertain significance | Hypercholesterolemia, familial, 1 | 2021-09-07 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV002486679 | SCV004831467 | uncertain significance | Hypercholesterolemia, familial, 1 | 2024-08-23 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Arg793Trp in the mature protein) replaces arginine with tryptophan at codon 814 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 an individual affected with early-onset myocardial infarction (PMID: 25487149). This variant has been identified in 2/251432 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. |