Total submissions: 7
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) |
LDLR- |
RCV000237850 | SCV000295037 | uncertain significance | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
U4M - |
RCV000237850 | SCV000583755 | pathogenic | Hypercholesterolemia, familial, 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
Fundacion Hipercolesterolemia Familiar | RCV000237850 | SCV000607518 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
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 |
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. |
Ce |
RCV003456385 | SCV004185155 | likely pathogenic | not provided | 2023-11-01 | criteria provided, single submitter | clinical testing | LDLR: PM1, PM2, PS4:Moderate, PS3:Supporting |