Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000238037 | SCV000295725 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Molecular Genetics Laboratory, |
RCV000238037 | SCV000540846 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000812951 | SCV000953281 | pathogenic | Familial hypercholesterolemia | 2018-09-04 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp662 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 15701167, 16159606, 22698793), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Experimental studies have shown that this missense change decreases LDL binding and uptake (PMID: 28645073). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 15701167, 27824480, 28645073, 22698793, Invitae. This variant is also known as p.D601N in the literature. ClinVar contains an entry for this variant (Variation ID: 252092). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 622 of the LDLR protein (p.Asp622Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. |
First Hospital of Lanzhou University, |
RCV000238037 | SCV004801928 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2024-02-23 | criteria provided, single submitter | clinical testing | A 38-year-old female proband carried a compliant heterozygous variant (c.292G>A,c.1864G> A and c.1448G> A, according to the ACMG guidelines they were separately classified as Uncertain significance, Likely pathogenic and pathogenic).The proband presented with a xanthoma, corneal aneurysm, and coronary artery diseaseThe patient's serum cholesterol concentration remained greater than 13 mmol/L after receiving intensive statin, Evolocumab and Inclisiran therapy.We speculate that the hepatocytes of the proband indicate the almostly absence of LDLR. The proband's mother, sister, and son all carried the c.292G>A,c.1864G> A variant. The proband father, both brothers and daughter carried the c.1448G> A variant. Without exception, all of her relatives showed hypercholesterolemia, but no atherosclerosis, xanthoma, or corneal aneurysm in the other relatives except the proband. Pedigree co-segregation evidence suggests that the three variants may be pathogenic variants in this familial hypercholesterolemic family. |