Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000238242 | SCV002817150 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2022-10-28 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.1301C>A (p.Thr434Lys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4_Supporting, PM2, PM5, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated cases, as follows: 1 case with DLCN >=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case with clinical criteria based on Defesche J. 2000. Familial hypercholesterolemia. In: Betteridge J (ed): Lipids and Vascular Disease from PMID 11810272. So PS4_Supporting is met. PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 is met. PM5: 3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) (ClinVar ID 251774) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1301C>T (p.Thr434Met)(ClinVar ID 251775) - Unknown significance by these guidelines - NM_000527.5(LDLR):c.1300A>C (p.Thr434Pro)(ClinVar ID 496018) - Unknown significance by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines. PP4: Variant meets PM2. Identified in 1 FH case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon with clinical DLCN Criteria score ≥ 6, after alternative causes of high cholesterol were excluded. |
| LDLR- |
RCV000238242 | SCV000295352 | likely benign | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Fundacion Hipercolesterolemia Familiar | RCV000238242 | SCV000607583 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004767192 | SCV005380479 | likely pathogenic | Familial hypercholesterolemia | 2024-08-21 | criteria provided, single submitter | clinical testing | Variant summary: LDLR c.1301C>A (p.Thr434Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251262 control chromosomes. c.1301C>A has been reported in the literature in an individual affected with Familial Hypercholesterolemia (Hobbs_1992, Fouchier_2001). This variant has also been reported in several heterozygous individual with familial hypercholesterolemia without clear clinical and family information for assessment (Marco-Bened_2021, Reijman_2023). A different variant affecting the same codon has been classified as pathogenic by our lab (c.1301C>G, p.Thr434Arg), supporting the critical relevance of codon 434 to LDLR protein function. One publication reports that LDL receptor activity in the patient carrying this variant is 5-15% of wild type protein activity. (Hobbs_1992). The following publications have been ascertained in the context of this evaluation (PMID: 1301956, 11810272, 34456049, 36752612). ClinVar contains an entry for this variant (Variation ID: 251773). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000238242 | SCV000606387 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |