Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000508725 | SCV002568026 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2022-08-28 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.269A>C (p.Asp90Ala) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM5_Strong, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM5_Strong - 4 other missense variants is the same codon: - NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) - classified as Likely pathogenic by the FH VCEP, with these guidelines - NM_000527.5(LDLR):c.269A>G (p.Asp90Gly) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) - Pathogenic by these guidelines There are 3 variants classified as Pathogenic by these guidelines, so PM5_Strong is met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP3 - REVEL = 0.964. It is above 0.75, so PP3 is met PP4 - Variant meets PM2, and was identified in 1 index case with SB criteria for FH (The clinical diagnosis of hoFH was confirmed on the basis of total cholesterol >500 mg/dl at the time of diagnosis, the presence of xanthomas at an early age, and the presence of primary hypercholesterolemia in the probands’ parents or other first degree relatives. This case had total cholesterol 840mg/dl at 3 years of age) from PMID 19026292 (Kolansky et al., 2008), USA so PP4 is met |
| Ambry Genetics | RCV002431468 | SCV002742714 | pathogenic | Cardiovascular phenotype | 2024-02-02 | criteria provided, single submitter | clinical testing | The p.D90A pathogenic mutation (also known as c.269A>C), located in coding exon 3 of the LDLR gene, results from an A to C substitution at nucleotide position 269. The aspartic acid at codon 90 is replaced by alanine, an amino acid with dissimilar properties. This variant (also described as legacy p.D69A) has been reported in individuals with hypercholesterolemia (Ambry internal data; Kolansky DM et al. Am. J. Cardiol., 2008 Dec;102:1438-43). Other alterations at the same codon including p.D90N (c.268G>A) and p.D90E (c.270T>A) have also been detected in individuals with familial hypercholesterolemia (Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Rubinsztein DC et al. Biochim. Biophys. Acta, 1993 Aug;1182:75-82). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. 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. |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000508725 | SCV000606057 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |