subjects mutated among 2600 FH index cases screened = 3 / FH-Potenza-2 / Software predictions: Damaging
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1118G>A (p.Gly373Asp)
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.
(14)
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
14
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.1118G>A (p.Gly373Asp)
Variation ID: 251673 Accession: VCV000251673.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11111571 (GRCh38) [ NCBI UCSC ] 19: 11222247 (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 Jul 29, 2016 Jul 23, 2024 May 13, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.1118G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Gly373Asp missense NM_001195798.2:c.1118G>A NP_001182727.1:p.Gly373Asp missense NM_001195799.2:c.995G>A NP_001182728.1:p.Gly332Asp missense NM_001195800.2:c.614G>A NP_001182729.1:p.Gly205Asp missense NM_001195803.2:c.737G>A NP_001182732.1:p.Gly246Asp missense NC_000019.10:g.11111571G>A NC_000019.9:g.11222247G>A NG_009060.1:g.27191G>A LRG_274:g.27191G>A LRG_274t1:c.1118G>A LRG_274p1:p.Gly373Asp P01130:p.Gly373Asp - Protein change
- G373D, G246D, G205D, G332D
- Other names
-
FH Potenza-2
- Canonical SPDI
- NC_000019.10:11111570:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
- 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 (9) |
criteria provided, multiple submitters, no conflicts
|
Jun 29, 2021 | RCV000237895.12 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 27, 2024 | RCV000791447.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 17, 2021 | RCV002436075.2 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
May 13, 2024 | RCV002243924.6 |
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: SCV000295229.2
First in ClinVar: Jul 29, 2016 Last updated: Oct 10, 2018 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Number of individuals with the variant: 1
Observation 4:
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Dec 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503300.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 3 / FH-Potenza-2 / Software predictions: Damaging
Number of individuals with the variant: 3
|
|
|
Pathogenic
(Mar 30, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583791.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016
Comment:
ACMG Guidelines: Pathogenic (ii)
|
Number of individuals with the variant: 9
Clinical Features:
Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present)
Indication for testing: Familial Hypercholesterolemia
Sex: mixed
Geographic origin: France
Comment on evidence:
Dutch Lipid Clinic Scoring : Probable FH
Secondary finding: no
|
|
|
Likely pathogenic
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588555.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
|
|
|
Likely pathogenic
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607560.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
|
Likely pathogenic
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Iberoamerican FH Network
Accession: SCV000748096.1
First in ClinVar: May 19, 2018 Last updated: May 19, 2018
Comment:
Variant present in the database from Argentina
|
|
|
|
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: SCV001653621.1
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
|
|
|
Pathogenic
(Nov 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000825010.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 373 of the LDLR protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 373 of the LDLR protein (p.Gly373Asp). This variant is present in population databases (no rsID available, gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9974426, 11810272, 11933210, 15241806, 21382890, 23375686, 25461735). This variant is also known as p.Gly352Asp. ClinVar contains an entry for this variant (Variation ID: 251673). 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%. This variant disrupts the p.Gly373 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16159606, 20145306), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Feb 27, 2024)
|
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: SCV004813643.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
Variant summary: LDLR c.1118G>A (p.Gly373Asp), also referred to as p.Gly352Asp, results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the … (more)
Variant summary: LDLR c.1118G>A (p.Gly373Asp), also referred to as p.Gly352Asp, results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) 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 3.1e-06 in 1613724 control chromosomes (gnomAD). c.1118G>A has been reported in the literature in at least two homozygous individuals and multiple heterozygous individuals affected with Familial Hypercholesterolemia (e.g. Bertolini_1999, Bertolini_2000, Fouchier_2001, Mozas_2004, Di Taranto_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9974426, 10978268, 34297352, 11810272, 15241806). ClinVar contains an entry for this variant (Variation ID: 251673). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely Pathogenic
(Jun 29, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848515.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Gly373Asp variant in LDLR, also described as p.Gly352Asp in the literature, has been previously reported in >15 individuals with hypercholesterolemia, including 1 individual with … (more)
The p.Gly373Asp variant in LDLR, also described as p.Gly352Asp in the literature, has been previously reported in >15 individuals with hypercholesterolemia, including 1 individual with familial hypercholesterolemia (FH) and tendon xanthoma who was homozygous for the variant, and segregated in at least 1 affected family member (Bertolini 1999 PMID: 9974426, Fouchier 2001 PMID: 11810272, Salazar 2002 PMID: 11933210, Mozas 2004 PMID: 15241806, van der Graaf 2011 PMID: 21382890, Bertolini 2013 PMID: 23375686, Jannes 2015 PMID: 25461735, Scicali 2017 PMID: 28958694, Corral 2018 PMID: 30270055). It has also been reported in 1 individual with early onset myocardial infarction (Khera 2019 PMID: 30586733). This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 251673) and has been identified in 0.0004% (1/282736) of pan-ethnic chromosomes by gnomAD (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis support 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, PM2_Supporting, PP3, PM3_supporting. (less)
|
|
|
Pathogenic
(Nov 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002752727.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.G373D pathogenic mutation (also known as c.1118G>A), located in coding exon 8 of the LDLR gene, results from a G to A substitution at … (more)
The p.G373D pathogenic mutation (also known as c.1118G>A), located in coding exon 8 of the LDLR gene, results from a G to A substitution at nucleotide position 1118. The glycine at codon 373 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been detected in both the homozygous and heterozygous states in multiple individuals meeting diagnostic criteria for familial hypercholesterolemia (FH) (Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999 Feb;19:408-18; Mozas P et al. Hum. Mutat., 2004 Aug;24:187; Noto D et al. Pediatr. Res., 2010 Feb;67:200-4; Dušková L et al. Atherosclerosis, 2011 May;216:139-45; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Scicali R et al. Nutr Metab Cardiovasc Dis, 2018 01;28:35-43; Corral P et al. Atherosclerosis, 2018 10;277:256-261; Khera AV et al. Circulation, 2019 Mar;139:1593-1602; Di Taranto MD et al. Clin Genet, 2021 11;100:529-541). In addition, this alteration is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Likely pathogenic
(May 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002513575.5
First in ClinVar: May 21, 2022 Last updated: Jul 23, 2024 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(G352D) and FH Potenza-2; This variant is associated with the following publications: (PMID: 33258288, 30270055, 11810272, 11933210, 21382890, 30586733, WerutskyCA2023[Article], 37739193, 36464169, 9974426, 24529145, 15241806, 28958694, 33508743, 10978268, 25461735, 32977124, 23375686, 34037665, 35177841, 35339733, 34297352) (less)
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|
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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: SCV000606332.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001460269.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
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Comment:
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 373 of the LDLR protein (p.Gly373Asp). This variant is present in population databases (no rsID available, gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9974426, 11810272, 11933210, 15241806, 21382890, 23375686, 25461735). This variant is also known as p.Gly352Asp. ClinVar contains an entry for this variant (Variation ID: 251673). 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%. This variant disrupts the p.Gly373 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16159606, 20145306), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: LDLR c.1118G>A (p.Gly373Asp), also referred to as p.Gly352Asp, results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) 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 3.1e-06 in 1613724 control chromosomes (gnomAD). c.1118G>A has been reported in the literature in at least two homozygous individuals and multiple heterozygous individuals affected with Familial Hypercholesterolemia (e.g. Bertolini_1999, Bertolini_2000, Fouchier_2001, Mozas_2004, Di Taranto_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9974426, 10978268, 34297352, 11810272, 15241806). ClinVar contains an entry for this variant (Variation ID: 251673). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The p.Gly373Asp variant in LDLR, also described as p.Gly352Asp in the literature, has been previously reported in >15 individuals with hypercholesterolemia, including 1 individual with familial hypercholesterolemia (FH) and tendon xanthoma who was homozygous for the variant, and segregated in at least 1 affected family member (Bertolini 1999 PMID: 9974426, Fouchier 2001 PMID: 11810272, Salazar 2002 PMID: 11933210, Mozas 2004 PMID: 15241806, van der Graaf 2011 PMID: 21382890, Bertolini 2013 PMID: 23375686, Jannes 2015 PMID: 25461735, Scicali 2017 PMID: 28958694, Corral 2018 PMID: 30270055). It has also been reported in 1 individual with early onset myocardial infarction (Khera 2019 PMID: 30586733). This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 251673) and has been identified in 0.0004% (1/282736) of pan-ethnic chromosomes by gnomAD (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis support 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, PM2_Supporting, PP3, PM3_supporting.
Comment:
The p.G373D pathogenic mutation (also known as c.1118G>A), located in coding exon 8 of the LDLR gene, results from a G to A substitution at nucleotide position 1118. The glycine at codon 373 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been detected in both the homozygous and heterozygous states in multiple individuals meeting diagnostic criteria for familial hypercholesterolemia (FH) (Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999 Feb;19:408-18; Mozas P et al. Hum. Mutat., 2004 Aug;24:187; Noto D et al. Pediatr. Res., 2010 Feb;67:200-4; Dušková L et al. Atherosclerosis, 2011 May;216:139-45; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Scicali R et al. Nutr Metab Cardiovasc Dis, 2018 01;28:35-43; Corral P et al. Atherosclerosis, 2018 10;277:256-261; Khera AV et al. Circulation, 2019 Mar;139:1593-1602; Di Taranto MD et al. Clin Genet, 2021 11;100:529-541). In addition, this alteration is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(G352D) and FH Potenza-2; This variant is associated with the following publications: (PMID: 33258288, 30270055, 11810272, 11933210, 21382890, 30586733, WerutskyCA2023[Article], 37739193, 36464169, 9974426, 24529145, 15241806, 28958694, 33508743, 10978268, 25461735, 32977124, 23375686, 34037665, 35177841, 35339733, 34297352)
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
subjects mutated among 2600 FH index cases screened = 3 / FH-Potenza-2 / Software predictions: Damaging
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 373 of the LDLR protein (p.Gly373Asp). This variant is present in population databases (no rsID available, gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9974426, 11810272, 11933210, 15241806, 21382890, 23375686, 25461735). This variant is also known as p.Gly352Asp. ClinVar contains an entry for this variant (Variation ID: 251673). 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%. This variant disrupts the p.Gly373 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16159606, 20145306), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: LDLR c.1118G>A (p.Gly373Asp), also referred to as p.Gly352Asp, results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) 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 3.1e-06 in 1613724 control chromosomes (gnomAD). c.1118G>A has been reported in the literature in at least two homozygous individuals and multiple heterozygous individuals affected with Familial Hypercholesterolemia (e.g. Bertolini_1999, Bertolini_2000, Fouchier_2001, Mozas_2004, Di Taranto_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9974426, 10978268, 34297352, 11810272, 15241806). ClinVar contains an entry for this variant (Variation ID: 251673). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The p.Gly373Asp variant in LDLR, also described as p.Gly352Asp in the literature, has been previously reported in >15 individuals with hypercholesterolemia, including 1 individual with familial hypercholesterolemia (FH) and tendon xanthoma who was homozygous for the variant, and segregated in at least 1 affected family member (Bertolini 1999 PMID: 9974426, Fouchier 2001 PMID: 11810272, Salazar 2002 PMID: 11933210, Mozas 2004 PMID: 15241806, van der Graaf 2011 PMID: 21382890, Bertolini 2013 PMID: 23375686, Jannes 2015 PMID: 25461735, Scicali 2017 PMID: 28958694, Corral 2018 PMID: 30270055). It has also been reported in 1 individual with early onset myocardial infarction (Khera 2019 PMID: 30586733). This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 251673) and has been identified in 0.0004% (1/282736) of pan-ethnic chromosomes by gnomAD (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis support 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, PM2_Supporting, PP3, PM3_supporting.
Comment:
The p.G373D pathogenic mutation (also known as c.1118G>A), located in coding exon 8 of the LDLR gene, results from a G to A substitution at nucleotide position 1118. The glycine at codon 373 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been detected in both the homozygous and heterozygous states in multiple individuals meeting diagnostic criteria for familial hypercholesterolemia (FH) (Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999 Feb;19:408-18; Mozas P et al. Hum. Mutat., 2004 Aug;24:187; Noto D et al. Pediatr. Res., 2010 Feb;67:200-4; Dušková L et al. Atherosclerosis, 2011 May;216:139-45; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Scicali R et al. Nutr Metab Cardiovasc Dis, 2018 01;28:35-43; Corral P et al. Atherosclerosis, 2018 10;277:256-261; Khera AV et al. Circulation, 2019 Mar;139:1593-1602; Di Taranto MD et al. Clin Genet, 2021 11;100:529-541). In addition, this alteration is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(G352D) and FH Potenza-2; This variant is associated with the following publications: (PMID: 33258288, 30270055, 11810272, 11933210, 21382890, 30586733, WerutskyCA2023[Article], 37739193, 36464169, 9974426, 24529145, 15241806, 28958694, 33508743, 10978268, 25461735, 32977124, 23375686, 34037665, 35177841, 35339733, 34297352)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic spectrum of familial hypercholesterolemia and correlations with clinical expression: Implications for diagnosis improvement. | Di Taranto MD | Clinical genetics | 2021 | PMID: 34297352 |
| Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases. | Quaio CRDC | American journal of medical genetics. Part C, Seminars in medical genetics | 2020 | PMID: 33258288 |
| Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. | Bertolini S | Atherosclerosis | 2020 | PMID: 32977124 |
| Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction. | Khera AV | Circulation | 2019 | PMID: 30586733 |
| Unusual genetic variants associated with hypercholesterolemia in Argentina. | Corral P | Atherosclerosis | 2018 | PMID: 30270055 |
| Detecting familial hypercholesterolemia by serum lipid profile screening in a hospital setting: Clinical, genetic and atherosclerotic burden profile. | Scicali R | Nutrition, metabolism, and cardiovascular diseases : NMCD | 2018 | PMID: 28958694 |
| Familial hypercholesterolemia in Brazil: cascade screening program, clinical and genetic aspects. | Jannes CE | Atherosclerosis | 2015 | PMID: 25461735 |
| Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
| Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children. | van der Graaf A | Circulation | 2011 | PMID: 21382890 |
| An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia. | Dušková L | Atherosclerosis | 2011 | PMID: 21310417 |
| Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations. | Chmara M | Journal of applied genetics | 2010 | PMID: 20145306 |
| Plasma non-cholesterol sterols: a useful diagnostic tool in pediatric hypercholesterolemia. | Noto D | Pediatric research | 2010 | PMID: 20091938 |
| Genetic screening protocol for familial hypercholesterolemia which includes splicing defects gives an improved mutation detection rate. | Graham CA | Atherosclerosis | 2005 | PMID: 16159606 |
| Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR. | Mozas P | Human mutation | 2004 | PMID: 15241806 |
| The UMD-LDLR database: additions to the software and 490 new entries to the database. | Villéger L | Human mutation | 2002 | PMID: 12124988 |
| Molecular basis of familial hypercholesterolemia in Brazil: Identification of seven novel LDLR gene mutations. | Salazar LA | Human mutation | 2002 | PMID: 11933210 |
| The molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human genetics | 2001 | PMID: 11810272 |
| Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype. | Bertolini S | Arteriosclerosis, thrombosis, and vascular biology | 2000 | PMID: 10978268 |
| Analysis of LDL receptor gene mutations in Italian patients with homozygous familial hypercholesterolemia. | Bertolini S | Arteriosclerosis, thrombosis, and vascular biology | 1999 | PMID: 9974426 |
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Text-mined citations for this variant ...
HelpRecord last updated Sep 29, 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.