ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1586+5G>A (rs781362878)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237174 SCV000295512 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237174 SCV000503370 uncertain significance Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 2
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237174 SCV000583852 likely pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Fundacion Hipercolesterolemia Familiar RCV000237174 SCV000607609 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000587894 SCV000697204 uncertain significance not provided 2017-04-25 criteria provided, single submitter clinical testing Variant summary: The LDLR c.1586+5G>A variant involves the alteration of a conserved intronic nucleotide that is 5 nucleotides away from the exon-intron junction. 4/5 splice prediction tools predict a significant impact on normal splicing and ESE finder predicts that the variant may cause an SRp55 ESE site to be introduced at the locus. One functional study has shown that the variant causes two aberrant splicing transcripts in several heterozygous patient cell lines and that the variant segregates with disease within two families, although several family members are discordant. This study also showed that LDL receptor was not properly trafficked to the cell surface in transfected COS7 cells (Jensen_CG_1999). However, a second functional study also detected aberrant splicing, but assessed LDL receptor protein function in heterozygous patient-derived lymphoblast cell lines and found that ~75% or greater of LDLR was at the cell surface and LDL was internalized similarly to controls, suggesting the variant transcripts do not have a significant biological impact (Holla_MGM_2009). Additionally, several studies have cited the variant in hypercholesterolemia patients, though cosegregation data is lacking in most cases. Based on the literature data, the variant may represent a mild mutation and may have a potentiated effect in compound heterozygosity with a truly pathogenic mutation, but have a less severe impact in heterozygous patients. This variant was found in the large control database ExAC at a frequency of 0.000034 (4/117662 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0010005). Multiple clinical diagnostic laboratories/reputable databases have classified this variant with conflicting interpretations, including likely pathogenic and uncertain significance. Taken together, this variant is classified as VUS until more conclusive family segregation data and/or control data can be assessed.
Invitae RCV001044315 SCV001208106 likely pathogenic Familial hypercholesterolemia 2019-11-01 criteria provided, single submitter clinical testing This sequence change falls in intron 10 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs781362878, ExAC 0.02%). This variant has been observed in several individuals and families affected with hypercholesterolemia (PMID: 7635461, 10668928, 17539906, 19208450, 19446849, 25463123). This variant is also known as c.1592+5G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 251909). Experimental studies have shown that this sequence change results in alternate RNA splicing mechanisms that cause the activation of a cryptic splice site in intron 10 and/or skipping of exon 10. Additional studies have suggested that this sequence change causes defects in receptor transport in vitro. However, the LDLR activity in patient-derived cells has not been shown to be significantly reduced (PMID: 10668928, 19208450). A different variant affecting this nucleotide (c.1586+5G>C) has been determined to be pathogenic (PMID: 17964958, Invitae). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000237174 SCV001432658 uncertain significance Familial hypercholesterolemia 1 2019-06-05 criteria provided, single submitter research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237174 SCV000606461 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000587894 SCV000925125 pathogenic not provided 2017-12-11 no assertion criteria provided provider interpretation 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;, 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.

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