Total submissions: 12
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000237850 | SCV002817154 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2022-10-28 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.898A>G (p.Arg300Gly) variant is classified as likely Pathogenic variant for Familial Hypercholesterolemia by applying evidence code PM2, PS3 and PS4 supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2_Met : PopMax MAF = 0.00003 in European (Non-Finnish) exomes (gnomAD v2.1.1) PS3_Met : Level 1 assay: Study of the whole LDLR cycle in Heterologous cells (CHO-ldlA7 cells), WB+FACS+CLSM. LDLR expression was not statistically different as compared to control. Conversely, LDL binding (<60%) and uptake (<60%) were significantly decreased (P<0.001). Interestingly, although the variant affects LDL binding and uptake, do not affect VLDL uptake. This reveals that the conformational change occurring in the module does not propagate to the whole ligand binding domain. (from PMID:25545329) |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV005401400 | SCV006102515 | likely pathogenic | Familial hypercholesterolemia | 2025-06-12 | criteria provided, single submitter | clinical testing | Variant summary: LDLR c.898A>G (p.Arg300Gly) results in a non-conservative amino acid change in the encoded protein sequence. 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. The variant allele was found at a frequency of 1.2e-05 in 251386 control chromosomes. c.898A>G has been observed in individual(s) affected with autosomal recessive Familial Hypercholesterolemia (Alonso_2009, Alves_2020, Bertolini_2020, Pirillo_2017, Sanchez-Hernandez_2016). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced binding activity and LDL uptake versus WT in CHO-ldlA7 cells (Etxebarria_2015). The following publications have been ascertained in the context of this evaluation (PMID: 38523000, 19318025, 32757650, 32977124, 25545329, 28965616, 27784735). ClinVar contains an entry for this variant (Variation ID: 251510). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Color Diagnostics, |
RCV005401400 | SCV006063233 | likely pathogenic | Familial hypercholesterolemia | 2024-05-07 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with glycine at codon 300 of the LDLR protein. This variant is also known as p.Arg279Gly in the mature protein. This variant alters a conserved arginine residue in the LDLR type A repeat 7 of the LDLR protein (a.a. 274-314), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Functional studies in LDLR-deficient cells indicated that this variant resulted in normal LDLR expression, but caused partial impairment (~50-60%) in LDL binding and uptake compared to wild-type LDLR (PMID: 25545329). This variant has been reported in more than ten heterozygous individuals affected with familial hypercholesterolemia (PMID: 19446849, 23375686, 27578128, 27784735, 28965616, 30293936, 32757650; ClinVar SCV002572850.1; SCV000583755.1). This variant has also been observed in homozygous state in three individuals affected with severe homozygous familial hypercholesterolemia (PMID: 27578128, 27784735, 32757650, 38523000). This variant has been identified in 3/251386 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
| Gene |
RCV003456385 | SCV005201883 | likely pathogenic | not provided | 2024-01-11 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies of the whole LDLR cycle performed in heterologous cells demonstrate a damaging effect through decreased LDL binding (55%) and uptake (60%) compared to wild type (PMID: 25545329); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.R279G; This variant is associated with the following publications: (PMID: 23375686, 32977124, 19318025, 30710474, 19446849, 28965616, 25545329) |
| Ambry Genetics | RCV004020954 | SCV005035841 | uncertain significance | Cardiovascular phenotype | 2023-11-17 | criteria provided, single submitter | clinical testing | The p.R300G variant (also known as c.898A>G), located in coding exon 6 of the LDLR gene, results from an A to G substitution at nucleotide position 898. The arginine at codon 300 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in individuals with familial hypercholesterolemia (FH) (Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). Additionally, an in vitro assay showed this alteration may reduce protein function (Etxebarria A et al. Atherosclerosis, 2015 Feb;238:304-12). This amino acid position is 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. |
| All of Us Research Program, |
RCV000237850 | SCV004841081 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2024-08-23 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with glycine at codon 300 of the LDLR protein. This variant is also known as p.Arg279Gly in the mature protein. This variant alters a conserved arginine residue in the LDLR type A repeat 7 of the LDLR protein (a.a. 274-314), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Functional studies in LDLR-deficient cells indicated that this variant resulted in normal LDLR expression, but caused partial impairment (~50-60%) in LDL binding and uptake compared to wild-type LDLR (PMID: 25545329). This variant has been reported in more than ten heterozygous individuals affected with familial hypercholesterolemia (PMID: 19446849, 23375686, 27578128, 27784735, 28965616, 30293936, 32757650; ClinVar SCV002572850.1; SCV000583755.1). This variant has also been observed in homozygous state in three individuals affected with severe homozygous familial hypercholesterolemia (PMID: 27578128, 27784735, 32757650, 38523000). This variant has been identified in 3/251386 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
| Ce |
RCV003456385 | SCV004185155 | likely pathogenic | not provided | 2023-11-01 | criteria provided, single submitter | clinical testing | LDLR: PM1, PM2, PS4:Moderate, PS3:Supporting |
| 3billion | RCV000237850 | SCV002572850 | pathogenic | Hypercholesterolemia, familial, 1 | 2022-09-01 | 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: 0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 25545329). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.56; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with LDLR -related disorder (ClinVar ID: VCV000251510 / PMID: 19318025). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 25545329 , 28965616 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |
| Greenwood Genetic Center Diagnostic Laboratories, |
RCV000237850 | SCV002499073 | pathogenic | Hypercholesterolemia, familial, 1 | 2022-02-21 | criteria provided, single submitter | clinical testing | PS3, PS4_Moderate, PM1, PM2 |
| Fundacion Hipercolesterolemia Familiar | RCV000237850 | SCV000607518 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
| U4M - |
RCV000237850 | SCV000583755 | pathogenic | Hypercholesterolemia, familial, 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
| LDLR- |
RCV000237850 | SCV000295037 | uncertain significance | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only |