rs137853966
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.653del(p.Gly218ValfsTer47) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000685 in 1,459,014 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
LDLR
NM_000527.5 frameshift
NM_000527.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.16
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 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-11105557-TG-T is Pathogenic according to our data. Variant chr19-11105557-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105557-TG-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.653del | p.Gly218ValfsTer47 | frameshift_variant | 4/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.653del | p.Gly218ValfsTer47 | frameshift_variant | 4/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459014Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 725588
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
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33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 07, 2021 | This frameshift variant causes the premature termination of LDLR protein synthesis. It has been reported in multiple individuals and families affected with hypercholesterolemia in the published literature (PMID: 7649546 (1995), 11668627 (2001), 19602640 (2009), 27765764 (2016)). Therefore, the variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 27, 2019 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Also reported as 1 bp deletion: G in codon 197, 652delG, and G197V->X243 due to alternate nomenclature; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 7649546, 11668627, 19602640, 27765764) - |
not provided, no classification provided | literature only | SNPedia | - | - - |
Hypercholesterolemia, familial, 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
Familial hypercholesterolemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 30, 2021 | This variant deletes 1 nucleotide in exon 4 of the LDLR gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 7649546, 11668627, 19602640, 26046366). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 2023 | This sequence change creates a premature translational stop signal (p.Gly218Valfs*47) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypercholesterolemia (PMID: 7649546, 27765764). ClinVar contains an entry for this variant (Variation ID: 68100). For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 12, 2017 | The c.653delG pathogenic mutation, located in coding exon 4 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 653, causing a translational frameshift with a predicted alternate stop codon (p.G218Vfs*47). This alteration has been reported in multiple hypercholesterolemia patients of various ethnic backgrounds (Giesel J et al. Hum. Genet., 1995 Sep;96:301-4; Wang J et al. Hum. Mutat., 2001 Oct;18:359; Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Day IN et al. Hum. Mutat., 1997;10:116-27). In addition to the clinical data reported in the literation, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at