Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000238136 | SCV000295820 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Molecular Genetics Laboratory, |
RCV000238136 | SCV000540852 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000810496 | SCV000950699 | uncertain significance | Familial hypercholesterolemia | 2021-08-27 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with serine at codon 675 of the LDLR protein (p.Gly675Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs770744861, ExAC 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11754108, 22698793, 27824480). This variant is also known as p.Gly654Ser. ClinVar contains an entry for this variant (Variation ID: 252173). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. |
| Color Diagnostics, |
RCV000810496 | SCV001360361 | uncertain significance | Familial hypercholesterolemia | 2023-01-31 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Gly654Ser in the mature protein) replaces glycine with serine at codon 675 of the LDLR protein. Computational prediction suggests that this variant may have 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: 11754108, 21310417, 22698793, 27824480). This variant has been identified in 1/249908 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 | RCV002418062 | SCV002724404 | likely pathogenic | Cardiovascular phenotype | 2018-05-04 | criteria provided, single submitter | clinical testing | The p.G675S variant (also known as c.2023G>A), located in coding exon 14 of the LDLR gene, results from a G to A substitution at nucleotide position 2023. The glycine at codon 675 is replaced by serine, an amino acid with similar properties. This alteration has been reported in individuals with familial hypercholesterolemia (Kuhrová V et al. Hum. Mutat., 2002 Jan;19:80; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |