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.
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1414G>T (p.Asp472Tyr)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(19)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
19
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.1414G>T (p.Asp472Tyr)
Variation ID: 183116 Accession: VCV000183116.31
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11113590 (GRCh38) [ NCBI UCSC ] 19: 11224266 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 28, 2015 Oct 20, 2024 Aug 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.1414G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Asp472Tyr missense NM_001195798.2:c.1414G>T NP_001182727.1:p.Asp472Tyr missense NM_001195799.2:c.1291G>T NP_001182728.1:p.Asp431Tyr missense NM_001195800.2:c.910G>T NP_001182729.1:p.Asp304Tyr missense NM_001195803.2:c.1033G>T NP_001182732.1:p.Asp345Tyr missense NC_000019.10:g.11113590G>T NC_000019.9:g.11224266G>T NG_009060.1:g.29210G>T LRG_274:g.29210G>T LRG_274t1:c.1414G>T LRG_274p1:p.Asp472Tyr - Protein change
- D472Y, D431Y, D304Y, D345Y
- Other names
- -
- Canonical SPDI
- NC_000019.10:11113589:G:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
functional variant; Sequence Ontology [ SO:0001536]disruptive missense [submitted by Dept. of Genetics and Pharmacogenomics, Merck Research Labs]
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00008
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4085 | 4361 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2024 | RCV000161988.16 | |
| Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Dec 18, 2023 | RCV000237883.28 | |
| Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 12, 2023 | RCV000775068.19 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Apr 7, 2021 | RCV000844749.12 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 6, 2024 | RCV002390395.9 | |
|
LDLR-related disorder
|
Likely pathogenic (1) |
no assertion criteria provided
|
Apr 23, 2024 | RCV004745231.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Mar 25, 2016)
|
criteria provided, single submitter
Method: literature only
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000295416.2
First in ClinVar: Jul 29, 2016 Last updated: Apr 09, 2018 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Dec 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001623423.2
First in ClinVar: May 23, 2021 Last updated: Feb 04, 2024 |
Comment:
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. … (more)
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. (less)
|
|
|
Likely pathogenic
(Nov 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001227232.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Likely pathogenic
(Sep 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000909169.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Likely pathogenic
(Nov 05, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
inherited
|
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Additional submitter:
Centre of Molecular Biology and Gene Therapy, University Hospital Brno
Accession: SCV000540817.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Number of individuals with the variant: 11
Clinical Features:
Hypercholesterolemia (present) , Xanthelasma (present) , Corneal arcus (present)
Family history: yes
Age: 10-55 years
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
|
|
|
Pathogenic
(Jun 22, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000234649.9
First in ClinVar: Jul 05, 2015 Last updated: Oct 09, 2016 |
Comment:
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; … (more)
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. (less)
|
|
|
Likely pathogenic
(May 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II
Accession: SCV001653634.1
First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Geographic origin: Italy
|
|
|
Likely pathogenic
(Apr 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Homozygous familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731720.3
First in ClinVar: Apr 09, 2018 Last updated: May 29, 2021 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 4
|
|
|
Likely pathogenic
(Nov 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022657.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Likely pathogenic
(Mar 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002702953.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
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 … (more)
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; Tichý, 2012; Bertolini, 2013; Vohnout, 2016; Gabová, 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. (less)
|
|
|
Pathogenic
(Aug 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005329923.2
First in ClinVar: Oct 08, 2024 Last updated: Oct 20, 2024 |
Comment:
LDLR: PP1:Strong, PM2, PM5, PS4:Moderate, PS3:Supporting
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(May 04, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888161.2
First in ClinVar: Oct 09, 2016 Last updated: Jan 01, 2022 |
|
|
|
Likely pathogenic
(Mar 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003920885.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
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 … (more)
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. (less)
|
|
|
Likely pathogenic
(Dec 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004227678.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1, PM2_supporting, PM3, PS3_supporting, PS4
Number of individuals with the variant: 1
|
|
|
Likely Pathogenic
(Dec 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004820314.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 7
|
|
|
Likely pathogenic
(Apr 23, 2024)
|
no assertion criteria provided
Method: clinical testing
|
LDLR-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005360022.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The LDLR c.1414G>T variant is predicted to result in the amino acid substitution p.Asp472Tyr. This variant is also known as p.Asp451Tyr in the literature and … (more)
The LDLR c.1414G>T variant is predicted to result in the amino acid substitution p.Asp472Tyr. This variant is also known as p.Asp451Tyr in the literature and has been reported in more than 10 individuals with familial hypercholesterolemia and myocardial infarction (Campagna et al. 2008. PubMed ID: 17196209; Tichý et al. 2012. PubMed ID: 22698793; Do et al. 2015. PubMed ID: 25487149; Vohnout et al. 2016. PubMed ID: 27542166; Hou et al. 2020. PubMed ID: 31980526). Functional studies suggested that p.Asp472Tyr substitution could impact normal protein function (Thormaehlen et al. 2015. PubMed ID: 25647241). This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD and has been interpreted as pathogenic and likely pathogenic by the vast majority of submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/183116/). Of note, a different variant impacting the same amino acid (p.Asp472Asn) has been reported to be associated with familial hypercholesterolemia (Marmontel et al. 2018. PubMed ID: 29572815). Based on this evidence, we interpret the c.1414G>T (p.Asp472Tyr) as likely pathogenic. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606418.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
|
not provided
(-)
|
no classification provided
(in vitro)
Method: in vitro
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not provided
Affected status: not applicable
Allele origin:
not applicable
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Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Accession: SCV000189563.1
First in ClinVar: Feb 28, 2015 Last updated: Feb 28, 2015
Comment:
In vitro functional profiling of LDL-receptor missense alleles identified through large-scale association testing
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Likely benign
(Dec 16, 2016)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Older and outlier claim with insufficient supporting evidence
Source: ClinGen
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503344.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting
Number of individuals with the variant: 1
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| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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; Tichý, 2012; Bertolini, 2013; Vohnout, 2016; Gabová, 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.
Comment:
LDLR: PP1:Strong, PM2, PM5, PS4:Moderate, PS3:Supporting
Comment:
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.
Comment:
PP1, PM2_supporting, PM3, PS3_supporting, PS4
Comment:
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.
Comment:
The LDLR c.1414G>T variant is predicted to result in the amino acid substitution p.Asp472Tyr. This variant is also known as p.Asp451Tyr in the literature and has been reported in more than 10 individuals with familial hypercholesterolemia and myocardial infarction (Campagna et al. 2008. PubMed ID: 17196209; Tichý et al. 2012. PubMed ID: 22698793; Do et al. 2015. PubMed ID: 25487149; Vohnout et al. 2016. PubMed ID: 27542166; Hou et al. 2020. PubMed ID: 31980526). Functional studies suggested that p.Asp472Tyr substitution could impact normal protein function (Thormaehlen et al. 2015. PubMed ID: 25647241). This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD and has been interpreted as pathogenic and likely pathogenic by the vast majority of submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/183116/). Of note, a different variant impacting the same amino acid (p.Asp472Asn) has been reported to be associated with familial hypercholesterolemia (Marmontel et al. 2018. PubMed ID: 29572815). Based on this evidence, we interpret the c.1414G>T (p.Asp472Tyr) as likely pathogenic.
Comment:
subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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has functional consequence
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Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Accession: SCV000189563.1
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Comment:
disruptive missense
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Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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; Tichý, 2012; Bertolini, 2013; Vohnout, 2016; Gabová, 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.
Comment:
LDLR: PP1:Strong, PM2, PM5, PS4:Moderate, PS3:Supporting
Comment:
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.
Comment:
PP1, PM2_supporting, PM3, PS3_supporting, PS4
Comment:
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.
Comment:
The LDLR c.1414G>T variant is predicted to result in the amino acid substitution p.Asp472Tyr. This variant is also known as p.Asp451Tyr in the literature and has been reported in more than 10 individuals with familial hypercholesterolemia and myocardial infarction (Campagna et al. 2008. PubMed ID: 17196209; Tichý et al. 2012. PubMed ID: 22698793; Do et al. 2015. PubMed ID: 25487149; Vohnout et al. 2016. PubMed ID: 27542166; Hou et al. 2020. PubMed ID: 31980526). Functional studies suggested that p.Asp472Tyr substitution could impact normal protein function (Thormaehlen et al. 2015. PubMed ID: 25647241). This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD and has been interpreted as pathogenic and likely pathogenic by the vast majority of submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/183116/). Of note, a different variant impacting the same amino acid (p.Asp472Asn) has been reported to be associated with familial hypercholesterolemia (Marmontel et al. 2018. PubMed ID: 29572815). Based on this evidence, we interpret the c.1414G>T (p.Asp472Tyr) as likely pathogenic.
Comment:
subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The Impact of Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies with and without Apheresis on Platelet Aggregation in Familial Hypercholesterolemia. | Konečný L | Cardiovascular drugs and therapy | 2024 | PMID: 37129685 |
| Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study. | Tromp TR | Lancet (London, England) | 2022 | PMID: 35101175 |
| Genomic Autopsy of Sudden Deaths in Young Individuals. | Webster G | JAMA cardiology | 2021 | PMID: 34379075 |
| Genetic spectrum of familial hypercholesterolemia and correlations with clinical expression: Implications for diagnosis improvement. | Di Taranto MD | Clinical genetics | 2021 | PMID: 34297352 |
| Comparison of the mutation spectrum and association with pre and post treatment lipid measures of children with heterozygous familial hypercholesterolaemia (FH) from eight European countries. | Futema M | Atherosclerosis | 2021 | PMID: 33508743 |
| Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. | Bertolini S | Atherosclerosis | 2020 | PMID: 32977124 |
| Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions. | Fahed AC | Nature communications | 2020 | PMID: 32820175 |
| Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
| Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: [email protected] | American journal of human genetics | 2019 | PMID: 31447099 |
| Detecting familial hypercholesterolemia earlier in life by actively searching for affected children:The DECOPIN project. | Ibarretxe D | Atherosclerosis | 2018 | PMID: 30312929 |
| Analysis of Children and Adolescents with Familial Hypercholesterolemia. | Minicocci I | The Journal of pediatrics | 2017 | PMID: 28161202 |
| The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey. | Gabčová D | Physiological research | 2017 | PMID: 27824480 |
| Genetic identification of familial hypercholesterolemia within a single U.S. health care system. | Abul-Husn NS | Science (New York, N.Y.) | 2016 | PMID: 28008010 |
| Genetic testing of familial hypercholesterolemia in a real clinical setting. | Vohnout B | Wiener klinische Wochenschrift | 2016 | PMID: 27542166 |
| Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction. | Thormaehlen AS | PLoS genetics | 2015 | PMID: 25647241 |
| Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. | Do R | Nature | 2015 | PMID: 25487149 |
| Inheritance pattern of familial hypercholesterolemia and markers of cardiovascular risk. | Kusters DM | Journal of lipid research | 2013 | PMID: 23833242 |
| Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
| The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. | Tichý L | Atherosclerosis | 2012 | PMID: 22698793 |
| An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia. | Dušková L | Atherosclerosis | 2011 | PMID: 21310417 |
| Nuclear factor-erythroid 2-related factor 2 as a chemopreventive target in colorectal cancer. | Saw CL | Expert opinion on therapeutic targets | 2011 | PMID: 21261563 |
| Detection of familial hypercholesterolemia in a cohort of children with hypercholesterolemia: results of a family and DNA-based screening. | Campagna F | Atherosclerosis | 2008 | PMID: 17196209 |
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Text-mined citations for rs730882102 ...
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Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.