rs540073140
Variant summary
Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1060+9C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code BP4 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: BP4: No Revel score. The variant does not affect splicing process, the variant is located out of range for all scenarios. LINK:https://erepo.genome.network/evrepo/ui/classification/CA031713/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1060+9C>T | intron_variant | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1060+9C>T | intron_variant | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000320 AC: 8AN: 250242Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135434
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1460500Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 726642
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152282Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74474
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:1Benign:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
Likely benign, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The c.1060+9C>T variant in LDLR has been reported in one individual with Familial Hypercholesterolemia in ClinVar (Variation ID: 369861), and has been identified in 0.04012% (8/19942) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs540073140). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 369861). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1_Supporting, BP4, BP7 (Richards 2015). - |
Uncertain significance, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Apr 28, 2023 | The NM_000527.5(LDLR):c.1060+9C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code BP4 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: BP4: No Revel score. The variant does not affect splicing process, the variant is located out of range for all scenarios. - |
Familial hypercholesterolemia Benign:3
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 14, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at