Description
p.Asp227Glyfs*12 (c.680_681delAC) in exon 4 of the LDLR gene (NM_000527.4; chr19-11216262-AC-) This variant is also known as 79-680delAC and p.D206fs in the literature. SCICD Classification: pathogenic variant based on mechanism of disease, strong case data and rarity in the general population. We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: LDLR: LDL receptors are located on the surface of the liver and play an important role in LDL recycling. Pathogenic variants in LDLR account for 80% of cases of familial hypercholesterolemia. Both missense and truncating/frameshift variants can be pathogenic. Case data (not including our patient): at least 6 patients with FH. ClinVar: Classified as pathogenic or likely pathogenic by 5 labs: LDLR-LOVD, British Heart Foundation, Robarts Research Institute,University of Western Ontario, Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, m voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum, CardiovasLaboratoriucular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital. Cases in the literature: Gudnason et al., 1993: 3 out of 200 patients with FH (2 of British origin, 1 Afrikaaner) Dedoussis et al., 2004: 1 out of 200 patients with FH (ancestry unclear - 100 German and 100 Greek patients). Wang et al., 2016: 1 out of 313 patients with FH. Bunn et al., 2002: A very similar deletion (c.679-680delAC) was present in 1 out of 150 patients with FH. Segregation data: none reported Functional data: none reported for this specific variant; however, truncating variants in LDLR are a known mechanism of disease. Conservation data: The asparagine at codon 227 is complete conserved across species. Neighboring amino acids are also completely conserved. Population data: Highest MAF in European population: 0.0009%. The variant was reported online in 1 of 122,394 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 55,342 individuals of European descent (MAF=0.0009). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).
| # | 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 |
