rs121908043
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM3PM2PP4PS4_SupportingPS3_Moderate
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1216C>A (p.Arg406=) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM3, PS3_Moderate, PP4 and PS4_Supportive) 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 - PopMax MAF = 0.00005441 (0.005%) in East Asian exomes (gnomAD v2.1.1).PM3 - Variant meets PM2 and is identified in one compound heterozygote with a homozygous FH phenotype published in PMID 28028493 (Patient F3 compound with NM_000527.5(LDLR):c.760C>T (p.Gln254Ter) (ClinVar ID 251436), LDLc: 18.21 mmol/l). Additional variant classified as Pathogenic by these guidelines.PS3_moderate - Level 2 FS: PMID:19371225 - Htz patient's Epstein-Barr virus transformed lymphocytes. RNA assays. Mutant mRNA 25%-45% of total amount.PP4 - Variant meets PM2. Variant identified in 2 index cases.PS4_supporting - Variant meets PM2. Variant identified in 2 index cases. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023436/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1216C>A | p.Arg406= | synonymous_variant | 9/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1216C>A | p.Arg406= | synonymous_variant | 9/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 29
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251046Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135832
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461294Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 726958
GnomAD4 genome ? Cov.: 29
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:8
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Dec 30, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2008 | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Jun 08, 2021 | The NM_000527.5(LDLR):c.1216C>A (p.Arg406=) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM3, PS3_Moderate, PP4 and PS4_Supportive) 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 - PopMax MAF = 0.00005441 (0.005%) in East Asian exomes (gnomAD v2.1.1). PM3 - Variant meets PM2 and is identified in one compound heterozygote with a homozygous FH phenotype published in PMID 28028493 (Patient F3 compound with NM_000527.5(LDLR):c.760C>T (p.Gln254Ter) (ClinVar ID 251436), LDLc: 18.21 mmol/l). Additional variant classified as Pathogenic by these guidelines. PS3_moderate - Level 2 FS: PMID: 19371225 - Htz patient's Epstein-Barr virus transformed lymphocytes. RNA assays. Mutant mRNA 25%-45% of total amount. PP4 - Variant meets PM2. Variant identified in 2 index cases. PS4_supporting - Variant meets PM2. Variant identified in 2 index cases. - |
Likely pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | Mar 03, 2019 | - - |
Pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, criteria provided, single submitter | curation;literature only | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of molecular diagnosis of dyslipidemias, UniversitĂ egli studi di Napoli Federico II | May 24, 2021 | altered splicing - |
Familial hypercholesterolemia Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 08, 2023 | This variant changes a single nucleotide in exon 9 (c.1216C>A) of the LDLR gene and has been shown to create a new splice acceptor site. RNA studies in cells from familial hypercholesterolemia subjects have shown that the usage of the newly created splice acceptor causes a deletion of 31 nucleotides from the beginning of exon 9 of the LDLR gene, leading to frameshift and premature truncation of the mutant allele (PMID: 17335829, 18400033). As a result, normal transcript is not produced from the mutant allele. This variant has been identified in multiple individuals diagnosed with familial hypercholesterolemia, mostly of Chinese origin (PMID: 17094996, 17335829, 18400033, 19371225, 21382890, 28028493, 28235710, 30270083, 31345425, 34037665, 34297352). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in multiple individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 36325061). This variant has been identified in 1/245992 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant at the same position (c.1216C>T) is also shown to cause splice defect (PMID: 28169869). Based on available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 10, 2017 | Variant summary: The LDLR c.1216C>A (p.Arg406Arg) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a significant impact on normal splicing by the introduction of a cryptic splice site and ESE finder predicts that this variant may affect ESE sites at the locus. In support of these predictions, functional studies have shown that the variant splice site is used preferentially over the wild type splice site in patient cell lines and in vitro splicing assays (Tveten_Genet Test Molec Biomarkers_2009; Bourbon_Ather_2007). Additionally, the variant has been cited in numerous patients with hypercholesterolemia and segregates with disease in families (e.g., van der Graaf_Circ_2011; Du_SpringerPlus_2016; Tveten_Genet Test Molec Biomarkers_2009). This variant is absent from the large control database ExAC and control cohorts from the literature (0/120510 control chromosomes). In addition, two reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | This sequence change affects codon 406 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LDLR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs121908043, gnomAD 0.006%). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 17094996, 17335829, 19371225, 21382890, 28028493). ClinVar contains an entry for this variant (Variation ID: 3746). Studies have shown that this variant results in a deletion of 31 base pairs of exon 9 and introduces a premature termination codon (PMID: 17335829, 19371225). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 23, 2024 | The c.1216C>A (p.R406R) alteration is located in coding exon 9 of the LDLR gene. This variant results from a C to A substitution at nucleotide position 1216. This nucleotide substitution does not change the arginine at codon 406. However, it is likely to have an effect on normal mRNA splicing. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in the heterozygous and compound heterozygous state in multiple individuals with heterozygous and homozygous familial hypercholesterolemia, respectively (Defesche, 2008; Fan, 2015; Du, 2016; Jiang, 2016; Xiang, 2017; Hsiung, 2018). This nucleotide position is highly conserved in available vertebrate species. Multiple functional studies indicate that the created cryptic acceptor site is preferentially utilized, resulting in a deletion of 31 nucleotides from the beginning of exon 9 and a frameshift (Bourbon, 2007; Defesche, 2008; Tveten, 2009). In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at