ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1186+5G>A

dbSNP: rs879254821
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000237711 SCV001960922 likely pathogenic Hypercholesterolemia, familial, 1 2021-06-08 reviewed by expert panel curation The NM_000527.5(LDLR):c.1186+5G>A variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_Moderate, PS4_Moderate 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: PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PS3_moderate - Level 2 FS: PMID:21990180 - study on htz patient's lymhocytes. FACS + CSLM + Nothern blot were used. 50% biosynthetic process; 65% binding; 60% clearance. Abnormal transcript: retention of part of intron 8 causing a frameshift and premature stop codon (LDLR:p.G396fs*26) then identified by cDNA sequencing. PS4_moderate - Variant meets PM2 and was found in 8 unrelated FH cases. PP4 - Variant meets PM2. Variant found in 8 FH cases fulfilling validated clinical criteria.
LDLR-LOVD, British Heart Foundation RCV000237711 SCV000295266 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237711 SCV000583800 likely pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Fundacion Hipercolesterolemia Familiar RCV000237711 SCV000607568 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000237711 SCV000748141 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Invitae RCV001039692 SCV001203233 likely pathogenic Familial hypercholesterolemia 2019-12-24 criteria provided, single submitter clinical testing This sequence change falls in intron 8 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 not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 12436241, 18096825). ClinVar contains an entry for this variant (Variation ID: 251706). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 21990180). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001039692 SCV001448367 pathogenic Familial hypercholesterolemia 2020-11-02 criteria provided, single submitter clinical testing Variant summary: LDLR c.1186+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes a 5' splicing donor site, one predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Etxebarria_2012). The variant was absent in 249224 control chromosomes (gnomAD). c.1186+5G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Etxebarria_2012, Amsellem_2002, Minicocci_2015, Kusters_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant causes decreased expression, LDL binding, and LDL internalization (Etxebarria_2012). Five submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as pathogenic (1x) / likely pathogenic (2x), or VUS (2x). Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237711 SCV000606343 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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