19-11105346-C-T
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3PM1PS3_SupportingPM2
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.440C>T (p.Thr147Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3_Supporting, PM1, PM2, and PP3 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: PS3_Supporting: Level 3 assays: PMID 21865347: Htz Patient lymphocytes, FACS assays - results - 55-70% LDLR activity---- results are below 85% of wild-type activity. So PS3_Supporting is met. PM1: Variant meets PM2 and is on exon 4. So PM1 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PP3: REVEL = 0.811. It is above 0.75, so PP3 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584919/MONDO:0007750/013
Frequency
Genomes: not found (cov: 33)
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
9
6
4
Clinical Significance
Conservation
PhyloP100: 5.71
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 Likely_pathogenic. Variant got 6 ACMG points.
PS3
For more information check the summary or visit ClinGen Evidence Repository.
PM1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.440C>T | p.Thr147Ile | missense_variant | 4/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
GnomAD4 genome
Cov.:
33
Bravo
AF:
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:8
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:5
| Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Mar 06, 2023 | PS3, PM2, PS4_Moderate, PP3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II | May 24, 2021 | Reduced activity in functional assays. - |
| Likely pathogenic, criteria provided, single submitter | curation;literature only | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | - - |
| Likely pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Apr 28, 2023 | The NM_000527.5(LDLR):c.440C>T (p.Thr147Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3_Supporting, PM1, PM2, and PP3 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: PS3_Supporting: Level 3 assays: PMID 21865347: Htz Patient lymphocytes, FACS assays - results - 55-70% LDLR activity ---- results are below 85% of wild-type activity. So PS3_Supporting is met. PM1: Variant meets PM2 and is on exon 4. So PM1 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PP3: REVEL = 0.811. It is above 0.75, so PP3 is met. - |
| Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
not provided Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Dec 21, 2021 | - - |
Cardiovascular phenotype Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 13, 2021 | The p.T147I variant (also known as c.440C>T), located in coding exon 4 of the LDLR gene, results from a C to T substitution at nucleotide position 440. The threonine at codon 147 is replaced by isoleucine, an amino acid with similar properties. This alteration was reported in two individuals from a familial hypercholesterolemia cohort and shown to reduce LDLR activity to 56% of normal levels in vivo (Romano M et al. J. Lipid Res., 2011 Nov;52:2095-100). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Familial hypercholesterolemia Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 16, 2023 | This missense variant (also known as p.Thr126Ile in the mature protein) replaces threonine with isoleucine at codon 147 in the LDLR type A repeat 4 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in a partial loss of LDLR function (PMID: 21865347). Threonine at this position is located in a functionally important region, and missense variants at this position are expected to interrupt glycosylation of linker regions in LDLR (PMID: 24798328). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 21865347, 34297352; Color internal data; communication with an external laboratory; ClinVar SCV002633357.1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.;M
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;.;.;.
Vest4
MutPred
Loss of glycosylation at T147 (P = 0.0164);Loss of glycosylation at T147 (P = 0.0164);.;Loss of glycosylation at T147 (P = 0.0164);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at