rs143872778
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. BP4BP7PM2
This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1836C>A (p.Ala612=) variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence code PM2, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - PopMax MAF = 0.00015 (0.015%) in East Asian exomes and genomes (gnomAD v2.1.1).Frequency is higher in "other" population exomes and genomes but number of allele is below 10000BP4 - No REVEL, splicing evaluation required.Functional data on splicing not available.- Variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT.- There is a GT nearby.MES scores: variant cryptic = -16.35, wt cryptic = -12.61, canonical donor = 4.48.Ratio variant cryptic/wt cryptic: -16.35/-12.61 = 1.30 --- it is above 1.1Ratio variant cryptic/canonical donor: -16.35/4.48 = -3.65 --- it is not above 0.9Variant is not predicted to alter splicing.BP7 - Variant is synonymous and meets BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA036811/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1836C>A | p.Ala612= | synonymous_variant | 12/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1836C>A | p.Ala612= | synonymous_variant | 12/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251468Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135904
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461852Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4AN XY: 727230
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74302
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Uncertain significance, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Mar 20, 2023 | NM_000527.5(LDLR):c.1836C>A (p.Ala612=) variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence code PM2, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00015 (0.015%) in East Asian exomes and genomes (gnomAD v2.1.1). Frequency is higher in "other" population exomes and genomes but number of allele is below 10000 BP4 - No REVEL, splicing evaluation required. Functional data on splicing not available. - Variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT. - There is a GT nearby. MES scores: variant cryptic = -16.35, wt cryptic = -12.61, canonical donor = 4.48. Ratio variant cryptic/wt cryptic: -16.35/-12.61 = 1.30 --- it is above 1.1 Ratio variant cryptic/canonical donor: -16.35/4.48 = -3.65 --- it is not above 0.9 Variant is not predicted to alter splicing. BP7 - Variant is synonymous and meets BP4. - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Familial hypercholesterolemia Uncertain:1Benign:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 17, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 01, 2023 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 16, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at