chr19-11102791-G-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_001406861.1(LDLR):c.576G>T(p.Lys192Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 31)
Consequence
LDLR
NM_001406861.1 missense
NM_001406861.1 missense
Scores
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.39
Genes affected
LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-11102791-G-T is Pathogenic according to our data. Variant chr19-11102791-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11102791-G-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.313+5G>T | splice_region_variant, intron_variant | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2
Likely 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 | - | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 25, 2024 | The LDLR c.313+5G>T variant has been reported in the published literature in individuals with hypercholesterolemia including a family with a homozygous father and his three heterozygous children (PMIDs: 16806138 (2006) and 26802169 (2016)). Also, an experimental study using a minigene splicing assay showed that this variant results in exon 3 skipping (PMID: 26802169 (2016)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper LDLR mRNA splicing. Based on the available information, this variant is classified as likely pathogenic. - |
Familial hypercholesterolemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 12, 2019 | This variant is located in intron 3 of the LDLR gene and changes a highly conserved nucleotide near the splice donor site. Computational splicing tools suggest that this variant may have significant impact on the RNA splicing. A mini-gene splicing assay has shown that this variant mainly causes an in-frame skipping of exon 3 (PMID: 26802169). LDLR exon 3 encodes the second LDLR type A repeat of the ligand binding domain, and absence of this exon is likely to have deleterious impact on LDLR function. This variant has been reported to segregate with disease in a Moroccan family affected with familial hypercholesterolemia (PMID: 16806138). In this family, homozygous father was reported with a very high level of LDL-C and suffered cerebrovascular disease at age 30 and had coronary manifestation (two myocardial infraction and two coronary bypasses) at age 35. His three heterozygous children were reported to be affected with hypercholesterolemia. This variant has also been identified in an unrelated individual affected with hypercholesterolemia (PMID: 26802169). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant at the same position (c.313+5G>A) has been shown to cause exon 3 skipping and has been associated with familial hypercholesterolemia (PMID: 11317362, 17094996). Based on available evidence, this variant is classified as Likely Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at