ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1414G>T (p.Asp472Tyr)

gnomAD frequency: 0.00001  dbSNP: rs730882102
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000161988 SCV000234649 pathogenic not provided 2016-06-22 criteria provided, single submitter clinical testing The D472Y c.1414 GAC>TAC variant in the LDLR gene has been published previously as a disease-causing variant in association with hypercholesterolemia (Campagna et al., 2008; Bertolini et al., 2013). Based on the ACMG recommendations, D472Y is interpreted as a known pathogenic sequence change.
LDLR-LOVD, British Heart Foundation RCV000237883 SCV000295416 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation RCV000237883 SCV000540817 likely pathogenic Hypercholesterolemia, familial, 1 2016-11-05 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000844749 SCV000731720 likely pathogenic Homozygous familial hypercholesterolemia 2021-04-07 criteria provided, single submitter clinical testing The p.Asp472Tyr variant in LDLR (also described as p.Asp451Tyr in the literature) has been reported in >15 individuals with familial hypercholesterolemia (FH) and 12 individuals who had a myocardial infarction, and segregated with disease in 3 affected relatives from 2 families (Abul-Husn 2016 PMID: 28008010, Vohnout 2016 PMID: 27542166, Thormaehlen 2015 PMID: 25647241, Tichy 2012 PMID: 22698793, Bertolini 2013 PMID: 23375686, Do 2015 PMID: 25487149, Campagna 2008 PMID: 17196209, ClinVar submission IDs: SCV000503344.1, SCV000540817.1). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 183116) and has been identified in 0.02% (5/30612) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein, and in vitro functional assays were unclear in their overall impact (Thormaehlen 2015 PMID: 25647241). 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 familial hypercholesterolemia. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP1.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000161988 SCV000888161 likely pathogenic not provided 2018-05-04 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000775068 SCV000909169 likely pathogenic Familial hypercholesterolemia 2023-09-11 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with tyrosine at codon 472 of the LDLR protein. This variant is also known as p.Asp451Tyr in the mature 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). A functional study has demonstrated that the mutant protein is partially defective in LDLR activity due to impaired protein expression or instability (PMID: 25647241). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 17196209, 17196209, 21310417, 22698793, 23375686, 27542166, 28008010, 27542166, 28008010, 35101175, 37129685; Fife 2021 https://doi.org/10.1101/2021.08.12.21261563; Alieva 2022, dissertation, University of Milan) and is reported to be associated with mild symptoms. This variant has also been shown to segregate with disease in two families (PMID: 17196209, 27542166). This variant has been identified in 15/282578 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000775068 SCV001227232 likely pathogenic Familial hypercholesterolemia 2023-11-17 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 472 of the LDLR protein (p.Asp472Tyr). This variant is present in population databases (rs730882102, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 17196209, 21310417, 22698793, 23375686, 27542166, 27824480, 28008010, 28161202). It has also been observed to segregate with disease in related individuals. This variant is also known as p.D451Y. ClinVar contains an entry for this variant (Variation ID: 183116). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 25647241). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000775068 SCV001623423 likely pathogenic Familial hypercholesterolemia 2023-12-12 criteria provided, single submitter clinical testing Variant summary: LDLR c.1414G>T (p.Asp472Tyr) results in a non-conservative amino acid change located in the class B repeat domain (IPR000033) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251206 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (5.6e-05 vs 0.0013), allowing no conclusion about variant significance. c.1414G>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g., Bertolini_2013, Futema_2021, Hou_2020, Tichy_2012, Abul-Husn_2016, DiTaranto_2021) where it is also shown to segregate with the disease in at least two families (e.g., Vohnoout_2016, Campagna_2008). These data indicate that the variant is likely to be associated with disease. At least one publication reports that the variant affects LDLR protein function, suggesting that the variant disrupts either LDLR biosynthesis or turnover (e.g., Thormaehlen_2015). The following publications have been ascertained in the context of this evaluation (PMID: 28008010, 23375686, 17196209, 34297352, 25487149, 21310417, 32820175, 33508743, 31980526, 30312929, 23833242, 25647241, 22698793, 27542166). Multiple submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, with 11 submitters classifying the variant as likely pathogenic/pathogenic and one submitter classifying it as likely benign. Additionally, there are other missense variants reported in the Human Gene Mutation Database (HGMD) affecting the same and/or nearby codons (example: p.S470C, p.D472N, p.I473N) associated with Hypercholesterolaemia suggesting this region may be clinically significant. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II RCV000237883 SCV001653634 likely pathogenic Hypercholesterolemia, familial, 1 2021-05-24 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000237883 SCV002022657 likely pathogenic Hypercholesterolemia, familial, 1 2022-11-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV002390395 SCV002702953 likely pathogenic Cardiovascular phenotype 2024-03-06 criteria provided, single submitter clinical testing The c.1414G>T (p.D472Y) alteration is located in exon 10 (coding exon 10) of the LDLR gene. This alteration results from a G to T substitution at nucleotide position 1414, causing the aspartic acid (D) at amino acid position 472 to be replaced by a tyrosine (Y). Based on data from gnomAD, the T allele has an overall frequency of 0.005% (15/282578) total alleles studied. The highest observed frequency was 0.016% (5/30612) of South Asian alleles. This variant has been reported in individuals with familial hypercholesterolemia and was reported to segregate with disease in two small families (Campagna, 2008; Tich&yacute;, 2012; Bertolini, 2013; Vohnout, 2016; Gabov&aacute;, 2017; Ibarretxe, 2018). This amino acid position is well conserved in available vertebrate species. A high-throughput in vitro assay suggested that this variant results in deficient protein function (Thormaehlen, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000237883 SCV003920885 likely pathogenic Hypercholesterolemia, familial, 1 2021-03-30 criteria provided, single submitter clinical testing LDLR NM_000527.4 exon 10 p.Asp472Tyr (c.1414G>T): This variant has been reported in the literature in the heterozygous state in several individuals with elevated LDL-C levels and/or a history of myocardial infaction, segregating with disease in multiple affected family members (Campagna 2008 PMID:17196209, Tichy 2012 PMID:22698793, Bertolini 2013 PMID:23375686, Do 2015 PMID:25487149, Thormaehlen 2015 PMID:25647241, Vohnout 2016 PMID:27542166). This variant is also present in 0.01% (5/30612) of South Asian alleles in the Genome Aggregation Database, including one homozygote (https://gnomad.broadinstitute.org/variant/19-11224266-G-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:183116). Evolutionary conservation suggests that this variant may not impact the protein, but computational predictive tools do suggest an impact. In addition, an in vitro functional study predicts that this variant will impact the protein (Thormaehlen 2015 PMID:25647241). However, this study may not accurately represent in vivo biological function. Of note, splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000161988 SCV004227678 likely pathogenic not provided 2022-12-07 criteria provided, single submitter clinical testing PP1, PM2_supporting, PM3, PS3_supporting, PS4
All of Us Research Program, National Institutes of Health RCV000237883 SCV004820314 likely pathogenic Hypercholesterolemia, familial, 1 2023-12-18 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with tyrosine at codon 472 of the LDLR protein. This variant is also known as p.Asp451Tyr in the mature 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). A functional study has demonstrated that the mutant protein is partially defective in LDLR activity due to impaired protein expression or instability (PMID: 25647241). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 17196209, 17196209, 21310417, 22698793, 23375686, 27542166, 28008010, 27542166, 28008010, 35101175, 37129685; Fife 2021 https://doi.org/10.1101/2021.08.12.21261563; Alieva 2022, dissertation, University of Milan) and is reported to be associated with mild symptoms. This variant has also been shown to segregate with disease in two families (PMID: 17196209, 27542166). This variant has been identified in 15/282578 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161988 SCV000189563 not provided not provided no assertion provided in vitro
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237883 SCV000503344 likely benign Hypercholesterolemia, familial, 1 2016-12-16 flagged submission clinical testing subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237883 SCV000606418 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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