rs138477254
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000527.5(LDLR):c.2282C>T(p.Thr761Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000533 in 1,614,132 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).
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.2282C>T | p.Thr761Met | missense_variant | Exon 15 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152174Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251242Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135844
GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461840Hom.: 0 Cov.: 34 AF XY: 0.0000536 AC XY: 39AN XY: 727216
GnomAD4 genome AF: 0.0000525 AC: 8AN: 152292Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74462
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:6Benign:2
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This missense variant (also known as p.Thr740Met in the mature protein) replaces threonine with methionine at codon 761 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). A functional study has shown that this variant does not disrupt LDLR function (PMID: 25647241). This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 15199436, 16250003, 16542394, 21722902), and in an individual affected with dyslipidemia (PMID: 32041611). This variant has been identified in 13/251242 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
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subjects mutated among 2600 FH index cases screened = 2/Software predictions: Conflicting -
not provided Uncertain:3Benign:1Other:1
In the published literature, this variant has been reported in individuals with familial hypercholesterolemia (PMIDs: 1722902 (2011), 16792510 (2006), 15199436 (2004), 21722902 (2011)). Additionally, the variant has been reported to co-occur with other pathogenic variants in individuals with familial hypercholesterolemia (PMIDs: 20428891 (2010), 18325082 (2008)). The frequency of this variant in the general population, 0.00018 (3/16248 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
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Observed in multiple individuals of different ethnic backgrounds with FH; however, at least two individuals also harbored additional variants in the LDLR gene (PMID: 15199436, 16250003, 16542394, 16792510, 19318025, 20428891, 21722902, 35913489); Observed in an individual with early myocardiac infarction, but normal LDL-C levels who underwent whole exome sequencing (PMID: 25487149, 25647241); Observed in a Dutch population in which carriers of this variant were concluded to have LDL-C levels that were not significantly different from non-carriers (PMID: 20506408, 22390909); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrated no change in LDL uptake in comparison to wild type LDLR protein (PMID: 25647241); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25647241, 16792510, 22390909, 25637381, 16250003, 16542394, 19318025, 21722902, 20428891, 15199436, 27044878, 32041611, 32719484, 25487149, 20506408, 35379577, 35913489, 18325082, 37409534) -
Familial hypercholesterolemia Pathogenic:1Uncertain:2
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This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 761 of the LDLR protein (p.Thr761Met). This variant is present in population databases (rs138477254, gnomAD 0.01%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 15199436, 16250003, 16542394, 18325082, 20428891, 22390909, 35379577, 35913489; internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be benign with a negative predictive value of at least 95%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 161262). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
This missense variant (also known as p.Thr740Met in the mature protein) replaces threonine with methionine at codon 761 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). A functional study has shown that this variant does not disrupt LDLR function (PMID: 25647241). This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 15199436, 16250003, 16542394, 21722902), and in an individual affected with dyslipidemia (PMID: 32041611). This variant has been identified in 13/251242 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not specified Uncertain:1
Variant summary: LDLR c.2282C>T (p.Thr761Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 246126 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in LDLR Familial Hypercholesterolemia (4.5e-05 vs 0.0013), allowing no conclusion about variant significance. The variant, c.2282C>T, has been reported in the literature in individuals affected with Familial Hypercholesterolemia and myocardial infarction (Thormaehlen_2015, Fouchier_2005, Brusgaard_2006, Amendola_2015). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Thormaehlen_2015). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS x4, pathogenic x1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Cardiovascular phenotype Uncertain:1
The p.T761M variant (also known as c.2282C>T), located in coding exon 15 of the LDLR gene, results from a C to T substitution at nucleotide position 2282. The threonine at codon 761 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in dyslipidemia and myocardial infarction cohorts (Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6; Lombardi MP et al. Genet Test, 2006;10:77-84; Brusgaard K et al. Clin Genet, 2006 Mar;69:277-83; Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6; Thormaehlen AS et al. PLoS Genet, 2015 Feb;11:e1004855; Dron JS et al. BMC Med Genomics, 2020 Feb;13:23). This alteration was detected in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 Aug;26:1235-1239). 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. -
Hypercholesterolemia Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at