Description
The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB and PCSK9. Results showed that the following variant was identified: - p.C173W (c.519C>G) in the LDLR gene. The lab classifies this as a pathogenic mutation. Given sufficient case data and it's disruption of the binding site of the low density lipoprotein receptor protein we consider this variant likely pathogenic and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least five unrelated cases of familial hypercholesterolemia (not including this patient's family). There is two generation segregation data presented in one family with four affected individuals. Couture, et al., 1998 reported a novel variant p.C173W (reported as p.C152W and c.519C>G in the paper). The C-to-G transversion at nucleotide 519 results in a change in the highly conserved cysteine at the C-terminal end in the fourth of the seven tandem cysteine repeats that for the binding site for LDLR (Bieri et al., 1995; Mehta et al., 1991). They variant segregated with FH in four individuals who had LDLs of 178, 298, 200 and 263, three of whom had tendinous xanthomas and two of which had coronary artery disease. Ebhardt, et al., 1999 reported a patient with p.C173W (reported as p.C152W and c.519C>G in the paper) in a Northern German individual that segregated with FH in the family (no details on number of individuals). Fouchier, et al., 2001; Morash, et al., 1998; Nauck, et al., 1997 all reported a patient with p.C173W (reported as p.C152W). The do not offer clinical details other than each patient had a diagnosis of familial hypercholesterolemia. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 1.00) and Mutation Taster predicts that it's disease causing (0.999). The cysteine at codon 173 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (C152R in a greek patient with compound heterozygous FH) and nearby codons (167, 175, and 177 in clinvar). In total the variant has not been seen in 100 published controls and individuals from publicly available population datasets. There is no missense variation at codon 173 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 24, 2015). There were 16,512 individuals of South Asian descent.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
