rs879254821
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS4_ModeratePM2PP4PS3_Moderate
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585344/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1186+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1186+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:4Uncertain:2
Likely pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Jun 08, 2021 | 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. - |
Uncertain significance, criteria provided, single submitter | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Uncertain significance, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
Familial hypercholesterolemia Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 04, 2023 | 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 251706). This variant is also known as IVS8+5G>A. This variant has been observed in individuals with familial hypercholesterolemia (PMID: 12436241, 18096825, 23833242, 26342331, 33740630; Invitae). This variant is not present in population databases (gnomAD no frequency). 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. It affects a nucleotide within the consensus splice site. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 02, 2020 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at