19-11123258-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_000527.5(LDLR):c.2225C>T(p.Thr742Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. T742A) has been classified as Likely benign.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.2225C>T | p.Thr742Ile | missense_variant | 15/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.2225C>T | p.Thr742Ile | missense_variant | 15/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251326Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135858
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461774Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727190
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152302Hom.: 0 Cov.: 30 AF XY: 0.0000134 AC XY: 1AN XY: 74458
ClinVar
Submissions by phenotype
Familial hypercholesterolemia Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 31, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2021 | This sequence change replaces threonine with isoleucine at codon 742 of the LDLR protein (p.Thr742Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs767546791, ExAC 0.002%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 11462246, 19837725). ClinVar contains an entry for this variant (Variation ID: 252259). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 15, 2023 | This missense variant (also known as p.Thr721Ile in the mature protein) replaces threonine with isoleucine at codon 742 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 11462246, 17142622) and in an individual affected with myocardial infarction (PMID: 34615865). This variant has been identified in 2/251326 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. - |
Hypercholesterolemia, familial, 1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | This missense variant (also known as p.Thr721Ile in the mature protein) replaces threonine with isoleucine at codon 742 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 11462246, 17142622) and in an individual affected with myocardial infarction (PMID: 34615865). This variant has been identified in 2/251326 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. - |
Likely benign, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 31, 2017 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Insufficient evidence for VUS5 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at