19-11116209-C-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):āc.1702C>Gā(p.Leu568Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000345 in 1,449,190 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 Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L568P) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1702C>G | p.Leu568Val | missense_variant | 11/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1702C>G | p.Leu568Val | missense_variant | 11/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000345 AC: 5AN: 1449190Hom.: 0 Cov.: 27 AF XY: 0.00000277 AC XY: 2AN XY: 721862
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Pathogenic, criteria provided, single submitter | curation;literature only | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | - - |
Familial hypercholesterolemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 568 of the LDLR protein (p.Leu568Val). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu568 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 20809525), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 251976). This variant is also known as p.L547V. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 10447263, 18718593, 25962062, 26510755). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 31, 2020 | This missense variant (also known as p.Leu547Val in the mature protein) replaces leucine with valine at codon 568 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). Computational splicing tools suggest that this variant may impact RNA splicing by activating a new splice donor site. This splice prediction has not been investigated in published RNA studies. It has been shown that this variant segregates with disease in 3 related individuals from a family affected with familial hypercholesterolemia (PMID: 26510755). This variant has been reported in multiple Japanese individuals affected with familial hypercholesterolemia (PMID: 10447263, 18718593, 26632531, 31491741) and is thought to occur at 3.4% of affected individuals, compared to 0.08% minor allele frequency in the general population in Japan (PMID: 18718593). This variant has also been identified in a Korean individual affected with familial hypercholesterolemia (PMID: 26343872). Carriers of this variant show very mild clinical phenotype due to ~75% residual LDL binding activity of the mutant protein (PMID: 18718593). 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. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 11, 2022 | The p.L568V variant (also known as c.1702C>G), located in coding exon 11 of the LDLR gene, results from a C to G substitution at nucleotide position 1702. The leucine at codon 568 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported as a heterozygote and compound heterozygote in familial hypercholesterolemia (FH) cohorts and has been reported in multiple family members in an affected family (Hattori H et al. Hum Mutat, 1999;14:87; Ohshiro T et al. J Atheroscler Thromb, 2010 Oct;17:1113; Miyagi Y et al. J Atheroscler Thromb, 2016 Oct;23:112-7; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909; Nagahara K et al. J Atheroscler Thromb, 2021 May). This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at