chr19-11105258-G-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000527.5(LDLR):c.352G>T(p.Asp118Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,302 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 (★★).
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.352G>T | p.Asp118Tyr | missense_variant | Exon 4 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250932Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135810
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461302Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 726974
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:5Uncertain:1
- -
- -
- -
- -
The c.352G>T (p.Asp118Tyr) variant of the LDLR gene, that encodes for low density lipoprotein receptor, has been identified in heterozygous status in several unrelated individuals (>10) who fulfill the clinical criteria of Familial Hypercholesterolemia (FH) (PMID:10978268, 11317362, 17196209, 20045108, 23375686, 28965616, 28958694). This variant has also been reported in homozygous or compound heterozygous status in multiple affected individuals (at least 6) with severe FH (PMID:10978268, 11317362, 23375686, 9974426, 28965616). In-vitro functional studies on cultured patient derived fibroblasts have shown that this variant results in 30% of normal LDLR activity when compound heterozygote with another well-known pathogenic variant, p.Val523Met (ClinVar ID: 3696) (PMID: 9974426, 23375686). This variant lies in the mutational hot spot (amino acids 105-232) of a well-established functional domain critical for LDLR protein function. This variant is found to be rare (3/250932; 0.00001196) in the general population database (gnomAD) and interpreted as likely pathogenic by several submitters in the ClinVar database (ClinVar ID: 183085). Therefore, the c.352G>T (p.Asp118Tyr) variant in LDLR gene is classified as likely pathogenic. -
- -
Familial hypercholesterolemia Pathogenic:3
Variant summary: LDLR c.352G>T (p.Asp118Tyr) 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 1.2e-05 in 250932 control chromosomes. c.352G>T has been reported in the literature in multiple heterozygous individuals affected with Familial Hypercholesterolemia, as well as multiple compound heterozygous individuals affected with Homozygous Familial Hypercholesterolemia (e.g., Bertolini_1999, Scicali_2018, Di Taranto_2020, Du_2022). These data indicate that the variant is very likely to be associated with disease. Two publications report experimental evidence evaluating an impact on protein function, however, none of these studies allow convincing conclusions about the variant effect. One study demonstrates that LDLR activity in an individual with the variant is approximately 30%, however this individual also carried the pathogenic variant p.V523M (Betolini_1999). Another study investigating whether this variant is disruptive demonstrated unclear results (Thormaehlen_2015). The following publications have been ascertained in the context of this evaluation (PMID: 9974426, 31947532, 36325061, 28958694, 25647241). ClinVar contains an entry for this variant (Variation ID: 183085). Based on the evidence outlined above, the variant was classified as pathogenic. -
This missense variant replaces aspartic acid with tyrosine at codon 118 of the LDLR protein. This variant is also known as p.Asp97Tyr in the mature protein, and FH Naples 3 in the literature. This variant alters a conserved AA1 residue in the LDLR type A repeat 3 of the LDLR protein (a.a. 107-145), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. A functional study has shown that this variant results in 30% of normal LDLR activity when in compound heterozygous state with a different pathogenic LDLR missense variant (PMID: 9974426). This variant has shown an unclear functional consequence in a high throughput screening assay in HeLa cells (PMID: 25647241). This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 9974426, 28161202, 28965616, 28958694, 31947532, 35795214; Color internal data). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in at least two individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 23375686, 31947532, 36325061). This variant has been identified in 3/250932 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 118 of the LDLR protein (p.Asp118Tyr). This variant is present in population databases (rs730882080, gnomAD 0.003%). This missense change has been observed in individuals with LDLR-related conditions (PMID: 9974426, 11317362, 23375686, 25487149, 28161202, 28965616, 31345425). 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 pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as D97Y, FH-Napoli-3 or Naples-3. ClinVar contains an entry for this variant (Variation ID: 183085). 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 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25647241). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2Other:1
- -
- -
Identified in the heterozygous and compound heterozygous state with a second LDLR variant in patients with hypercholesterolemia in published literature (PMID: 9974426, 28965616, 34297352, 35339733, 32977124); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(D97Y); This variant is associated with the following publications: (PMID: 9974426, 23375686, 25647241, 35339733, 25487149, 28965616, 34297352, 32977124, 30583242, 34906454) -
Homozygous familial hypercholesterolemia Pathogenic:1
The p.Asp118Tyr variant in LDLR has been identified in the heterozygous state in at least 6 individuals with hypercholesterolemia and segregated with disease in > 4 affected relatives with definite or probable familial hypercholesterolemia (FH) from at least 2 families (Bertolini 1999 PMID: 9974426, Bertolini 2000 PMID: 10978268, Liguori 2001 PMID: 11317362, Campagna 2008 PMID: 17196209, Romano 2010 PMID: 20045108, Bertolini 2013 PMID: 23375686, Scicali 2017 PMID: 28958694, Pirillo 2017 PMID: 28965616, Trinder 2019 PMID: 31345425). It has also been reported in 1 homozygote and 3 compound heterozygotes (with additional pathogenic LDLR variants) with hypercholesterolemia, at least 3 of whom had a more severe presentation (Bertolini 2000 PMID: 10978268, Liguori 2001 PMID: 11317362, Campagna 2008 PMID: 17196209, Bertolini 2013 PMID: 23375686). Additionally, this variant has been reported in 2 individuals with early myocardial infarction (Thormaehlen 2015 PMID: 25647241). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 183085) and has also been identified in 0.003% (3/111436) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies suggest that the variant has only a mild impact protein function (Bertolini 2013 PMID: 23375686, Thormaehlen 2015 PMID: 25647241). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4_Moderate, PM3, PP1, PM2_Supporting. -
Cardiovascular phenotype Pathogenic:1
The p.D118Y variant (also known as c.352G>T), located in coding exon 4 of the LDLR gene, results from a G to T substitution at nucleotide position 352. The aspartic acid at codon 118 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration, also known as p.D97Y, has been reported primarily in Italian familial hypercholesterolemia (FH) cohorts (Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999 Feb;19:408-18; Liguori R et al. Hum. Mutat., 2001 May;17:433; Campagna F et al. Atherosclerosis, 2008 Jan;196:356-64; Romano M et al. Atherosclerosis, 2010 Jun;210:493-6; Minicocci I et al. J. Pediatr., 2017 Apr;183:100-107.e3; Scicali R et al. Nutr Metab Cardiovasc Dis, 2018 Jan;28:35-43). Reduced LDL-R activity (30% of the control) was reported in a compound heterozygous FH patient who also carried the p.V523M pathogenic mutation (Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999 Feb;19:408-18). Based on internal structural analysis, this variant is predicted to disrupt a linear motif (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. 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