Description
c.1586+5G>A in intron 10 of the LDLR gene (NM_00527; chr19-11224443-G-A) SCICD Classification: pathogenic variant based on strong case data, strong segregation data and strong functional data. 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 25 cases, plus other family members. · ClinVar: § LDLR-LOVD, British Heart Foundation - likely pathogenic - 2 out of 2600 patients with FH have this variant § Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix - VUS § U4M - Lille University & CHRU Lille,Université Lille 2 - CHRU de Lille - likely pathogenic § Fundacion Hipercolesterolemia Familiar - VUS § Never seen at Invitae § Color Genomics has this variant in their "John Doe" report: they indicate that many algorithms predict a significant impact on the intron 10 donor · Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum - pathogenic · Cases in the literature: · Yang et al 2007: 87 Taiwanese individuals with FH from 30 unrelated families: seen in 2 families. Authors report that this variant may result in the skipping of exon 10. This variant segregated with disease in family members; however, the number of family members with which it segregates is unknown. · Ekström et al 1994: this variant (noted as c.1596+5G>A in this paper) was detected in 1 out of 7 children with FH. · Fouchier et al 2005: 1 out of 325 patients in the Dutch cohort · Taylor et al 2007: Found this variant in one out of 400 patients with FH. This particular patient had possible FH. · Guardamagna et al 2009: This variant was seen in one patient of the following cohort: 264 children from 201 families, 148 affected parents and 100 unaffected siblings. · Mollaki et al 2014: Variant detected in 1 out of 561 patients from 262 families · Jensen et al 1999: This variant is known as c.1596+5G>A in this paper. This variant was present in a 36yo Danish man presenting with tendon xanthomas, severe CAD, CABG at 24yo and very high LDL cholesterol. This man had another variant as well - p.T383P. This variant segregated with disease in his family members (pedigree A, FH-DK 8). Another family had only this variant and it segregated with disease. From the first family, this variant segregated with 8 affected individuals. From the second family, this variant segregated in 4 individuals. Segregation data: See above, Jensen et al 1999 Functional data: Jenner et 1999: sequence analysis of cDNA indicates that either i) a cryptic splice site is activated or ii) exon 10 is skipped: i) the donor splice site at the +5 position is activated to create a cryptic splice site which results in an in-frame insertion of 22 amino acids; ii) in-frame deletion of 75 amino acids in the EGF precursor homology domain of the LDL receptor protein. The authors predicted about 50% of these variants were spliced correctly, and 50% spliced incorrectly. To measure the amount of LDL receptor protein on the surface of the cells, fluorescence was used. Fluorescence of both of these mutant cell lines was markedly reduced in both of these cell lines compared to wildtype. Splice data (splice variants only): Buratti et al 2007: "...point mutations leading to cryptic 5' splice site activation were most common in the first intron nucleotide, followed by the fifth nucleotide. Substititons at position +5 were exclusively G>A transitions... The frequency of point mutations at position +5 was significantly higher than observed in[HGMD] suggesting that alterations of this position are particularly prone to aberrant splicing, possibly due to a requirement for sequential interactions with U1 and U6 snRNAs." Functional data above by Jensen and colleagues corroborates predictions that this variant impacts splicing. Conservation data: The G at position c.1586+5 is conserved among species. Population data: Highest MAF in South Asian population: 0.0195%. The variant was reported online in 8 of 122,672 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 6 of 15,376 individuals of South Asian descent (MAF=0.0195%) and 2 of 55,674 individuals of European descent. 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.
| # | 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 |
