Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002416922 | SCV002678033 | pathogenic | Cardiovascular phenotype | 2021-10-18 | criteria provided, single submitter | clinical testing | The p.D266H pathogenic mutation (also known as c.796G>C), located in coding exon 5 of the LDLR gene, results from a G to C substitution at nucleotide position 796. The aspartic acid at codon 266 is replaced by histidine, an amino acid with similar properties. This alteration impacts a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 6 (Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62). This variant has been detected in the compound heterozygous state in a pediatric case with homozygous familial hypercholesterolemia (FH) presentation including multiple xanthomas and LDL-C of 16.2mmol/L (Lin M et al. Cardiol Young, 2016 Jan;26:197-201). Other variants affecting this codon (p.D266E (c.798T>A) and p.D266N (c.796G>A), also referred to as p.D245E and p.D245N) have also been reported in association with FH (Schmidt H et al. Atherosclerosis 2000;148:431-2; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV003103462 | SCV003442713 | likely pathogenic | Familial hypercholesterolemia | 2022-03-28 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asp266 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 20663204, 21310417, 22698793, 23375686, 26238499). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 28235710, 29233637). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 266 of the LDLR protein (p.Asp266His). |