rs200793488
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.2230C>T(p.Arg744Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,012 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R744R) has been classified as Benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000527.5 stop_gained
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.2230C>T | p.Arg744Ter | stop_gained | 15/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.2230C>T | p.Arg744Ter | stop_gained | 15/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152154Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251326Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135874
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461740Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727190
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152272Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2AN XY: 74442
ClinVar
Submissions by phenotype
Familial hypercholesterolemia Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2023 | This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 29353225). ClinVar contains an entry for this variant (Variation ID: 430795). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg744*) 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 21, 2023 | This variant changes 1 nucleotide in exon 15 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 29353225, 35274909). This variant has been identified in 1/251326 chromosomes 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, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 30, 2021 | - - |
Hypercholesterolemia, familial, 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 08, 2023 | This variant changes 1 nucleotide in exon 15 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 29353225, 35274909). This variant has been identified in 1/251326 chromosomes 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. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 18, 2023 | The p.R744* pathogenic mutation (also known as c.2230C>T), located in coding exon 15 of the LDLR gene, results from a C to T substitution at nucleotide position 2230. This changes the amino acid from an arginine to a stop codon within coding exon 15. This variant has been detected in individuals from familial hypercholesterolemia cohorts, and has been reported to segregate with disease in a family (Garg A et al. J Endocr Soc, 2020 Jan;4:bvz015; Meshkov A et al. Genes (Basel), 2021 Jan;12; Leren TP et al. Atherosclerosis, 2021 Apr;322:61-66). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at