19-11116876-C-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000527.5(LDLR):c.1723C>T(p.Leu575Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L575P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1723C>T | p.Leu575Phe | missense_variant | 12/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1723C>T | p.Leu575Phe | missense_variant | 12/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251486Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135916
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461746Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 727172
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | Jan 02, 2018 | - - |
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Leu575Phe variant in LDLR has been reported in at least one individual with Familial Hypercholesterolemia (PMID: 27830735), and has been identified in 0.005437% (1/18394) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). 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: 438324). In vitro functional studies provide some evidence that the p.Leu575Phe variant may impact protein function (PMID: 27830735, 29874871). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_Moderate, PP3 (Richards 2015). - |
Likely pathogenic, criteria provided, single submitter | curation;literature only | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | - - |
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 12, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect on protein function (Jiang et al., 2016); This variant is associated with the following publications: (PMID: 29874871, 32041611, 33994402, 27830735, 33747976) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 13, 2019 | - - |
Familial hypercholesterolemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 02, 2022 | This missense variant (also known as p.Leu554Phe in the mature protein) replaces leucine with phenylalanine at codon 575 in the LDLR type B repeat 5 of the EGF precursor homology domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a defect in protein trafficking and results in reduced cell-surface expression of LDLR and diminished LDL binding/uptake activities (PMID: 27830735, 29874871). This variant has been reported in at least 6 unrelated individuals affected with familial hypercholesterolemia (PMID: 27830735, 28502495, 33994402, 33747976). It has been shown that this variant segregates with elevated LDL-C levels in a family with myocardial infarction, hyperlipidemia, hypertension, and type 2 diabetes mellitus (PMID: 33747976). This variant has been identified in 1/251486 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 07, 2022 | The p.L575F variant (also known as c.1723C>T), located in coding exon 12 of the LDLR gene, results from a C to T substitution at nucleotide position 1723. The leucine at codon 575 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been detected in familial hypercholesterolemia (FH) and mixed dyslipidemia cohorts; however, details were limited (Chiou KR et al. J Clin Lipidol, 2017 Jan;11:386-393.e6; Huang CC et al. J Atheroscler Thromb, 2022 May;29:639-653; Dron JS et al. BMC Med Genomics, 2020 Feb;13:23). This variant co-occurred with a second LDLR variant in a homozygous FH cohort; however, details were limited (Jiang L et al. Sci Rep, 2016 Nov;6:36823; Du Z et al. iScience, 2022 Nov;25:105334). Functional studies by one group suggest this variant may result in a moderate reduction in protein function (Jiang L et al. Sci Rep, 2016 Nov;6:36823). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at