Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000237488 | SCV000294985 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Centre de Génétique Moléculaire et Chromosomique, |
RCV000237488 | SCV000503240 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation / other mutation at same codon / Software predictions: Damaging |
| Molecular Genetics Laboratory, |
RCV000237488 | SCV000540760 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | Disrupt disulfide bridge between Cys255 and Cys270. |
| Laboratory of molecular diagnosis of dyslipidemias, |
RCV000237488 | SCV001653610 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2021-05-24 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001844101 | SCV002103530 | uncertain significance | not specified | 2022-02-12 | criteria provided, single submitter | clinical testing | Variant summary: LDLR c.808T>C (p.Cys270Arg) results in a non-conservative amino acid change located in the LDL-receptor class A6 domain (LOVD database) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251462 control chromosomes. c.808T>C has been reported in the literature as a heterozygous genotype in at-least one Czech individual with Familial Hypercholesterolemia (FH) who has been subsequently reported by others (example, Kuhrova_2002, Duskova_2011, Tichy_2012) and in at-least one Italian individual with FH (example, Di Taranto_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Different variants that alters the same codon (c.808T>A, p.Cys270Ser, c.809G>A, p.Cys270Tyr) and others that alter neighboring residues have been reported in individuals with Hypercholesterolemia suggesting that this residue and its location are essential for overall function. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, until additional clinical and functional data become available, the variant was classified as VUS-possibly pathogenic. |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237488 | SCV000606231 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |