The NM_000527.5(LDLR):c.58G>A (p.Gly20Arg) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BS3, BS4 and PP1_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BS2 - Variant identified in 5 unaffected relatives from Centre of molecular biology and gene therapy and 1 elderly heterozygous from the ABraOM database. BS3 - Level 1 assays: PMID 27175606: Heterologous cells (CHO), CLSM assays - result - normal cell surface LDLR, normal LDL-LDLR binding. ---- although not quantified, assume whole cycle is above 90% of wild-type, so BS3 is Met. BS4 - Variant does not segregate with FH phenotype in 8 informative meiosis from at least 3 families from different labs (Centre of molecular biology and gene therapy, University of British Columbia and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis from Centre of molecular biology and gene therapy. Variant has 3 strong evidence codes towards Benign, enough to classify as Benign, and only 1 moderate evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Benign.
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.58G>A (p.Gly20Arg)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Benign
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.58G>A (p.Gly20Arg)
Variation ID: 161272 Accession: VCV000161272.45
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11089606 (GRCh38) [ NCBI UCSC ] 19: 11200282 (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 Dec 7, 2014 Oct 20, 2024 Jun 7, 2021 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.58G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Gly20Arg missense NM_001195798.2:c.58G>A NP_001182727.1:p.Gly20Arg missense NM_001195799.2:c.58G>A NP_001182728.1:p.Gly20Arg missense NM_001195800.2:c.58G>A NP_001182729.1:p.Gly20Arg missense NM_001195803.2:c.58G>A NP_001182732.1:p.Gly20Arg missense NR_163945.1:n.54C>T non-coding transcript variant NC_000019.10:g.11089606G>A NC_000019.9:g.11200282G>A NG_009060.1:g.5226G>A LRG_274:g.5226G>A LRG_274t1:c.58G>A LRG_274p1:p.Gly20Arg - Protein change
- G20R
- Other names
-
NM_000527.5(LDLR):c.58G>A
- Canonical SPDI
- NC_000019.10:11089605:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
no known functional consequencenon-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.
-
0.00060 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00060
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00069
The Genome Aggregation Database (gnomAD), exomes 0.00074
Exome Aggregation Consortium (ExAC) 0.00105
1000 Genomes Project 30x 0.00047
Trans-Omics for Precision Medicine (TOPMed) 0.00052
The Genome Aggregation Database (gnomAD) 0.00053
- 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 | |
| LDLR-AS1 | - | - | - | GRCh38 | - | 204 |
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. |
|---|---|---|---|---|
| Benign (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2024 | RCV000161949.26 | |
| Benign (10) |
reviewed by expert panel
|
Jun 7, 2021 | RCV000211611.31 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jun 1, 2014 | RCV002051665.10 | |
| Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 31, 2020 | RCV000609054.12 | |
| Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000771169.18 | |
| Likely benign (1) |
criteria provided, single submitter
|
May 22, 2018 | RCV002354338.9 | |
|
LDLR-related disorder
|
Likely benign (1) |
no assertion criteria provided
|
Jun 2, 2024 | RCV003952707.2 |
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. |
|
|---|---|---|---|---|---|
|
Benign
(Jun 07, 2021)
|
reviewed by expert panel
Method: curation
|
Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV001960907.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Comment:
The NM_000527.5(LDLR):c.58G>A (p.Gly20Arg) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BS3, BS4 and PP1_Moderate) as defined by the ClinGen … (more)
The NM_000527.5(LDLR):c.58G>A (p.Gly20Arg) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BS3, BS4 and PP1_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BS2 - Variant identified in 5 unaffected relatives from Centre of molecular biology and gene therapy and 1 elderly heterozygous from the ABraOM database. BS3 - Level 1 assays: PMID 27175606: Heterologous cells (CHO), CLSM assays - result - normal cell surface LDLR, normal LDL-LDLR binding. ---- although not quantified, assume whole cycle is above 90% of wild-type, so BS3 is Met. BS4 - Variant does not segregate with FH phenotype in 8 informative meiosis from at least 3 families from different labs (Centre of molecular biology and gene therapy, University of British Columbia and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis from Centre of molecular biology and gene therapy. Variant has 3 strong evidence codes towards Benign, enough to classify as Benign, and only 1 moderate evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Benign. (less)
|
|
|
Uncertain significance
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000322872.1
First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016 |
Comment:
0/190 non-FH alleles; 0/150 normolipidemic chromosomes
Observation 1:
Comment on evidence:
%MAF (ExAC):0.1046
Observation 2:
Comment on evidence:
Heterologous cells (CHO), FACS assays
Result:
Normal cell surface LDLR, binding and uptake
|
|
|
Benign
(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: SCV000540713.1
First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016 |
Comment:
A functional analysis was previously published (Pavloušková et al, 2016). This variant has no effect on LDLR protein function.
Number of individuals with the variant: 27
Clinical Features:
Hypercholesterolemia (present) , Ischemic stroke (present)
Family history: yes
Age: 14-74 years
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
|
|
|
Uncertain significance
(Aug 16, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001288138.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Likely benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000556775.9
First in ClinVar: Apr 16, 2017 Last updated: Feb 28, 2024 |
|
|
|
Uncertain significance
(Jun 01, 2014)
|
criteria provided, single submitter
Method: research
|
Hypercholesterolaemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190291.2 First in ClinVar: Dec 07, 2014 Last updated: Dec 07, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
|
Comment:
Low GERP score may suggest that this variant may belong in a lower pathogenicity class
|
|
|
Likely benign
(Mar 25, 2016)
|
criteria provided, single submitter
Method: literature only
|
Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000294427.2
First in ClinVar: Jul 29, 2016 Last updated: May 26, 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
Observation 5:
Number of individuals with the variant: 1
Observation 6:
Number of individuals with the variant: 1
Observation 7:
Number of individuals with the variant: 1
Observation 8:
Number of individuals with the variant: 1
Observation 9:
Number of individuals with the variant: 1
Observation 10:
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Feb 19, 2016)
|
criteria provided, single submitter
Method: research
|
Hypercholesterolemia, familial, 1
2 cases with mild hypercholesterolemia
Affected status: no
Allele origin:
germline
|
Cardiovascular Biomarker Research Laboratory, Mayo Clinic
Study: RIGHT
Accession: SCV000266321.2 First in ClinVar: Mar 24, 2016 Last updated: Apr 16, 2017 |
Comment:
MAF =<0.3%. "Little/No effect" on the LDL receptor activity based on experimental validation.
Indication for testing: Familial hypercholesterolemia
Age: 55-66 years
Sex: male
Ethnicity/Population group: White
Geographic origin: United States
|
|
|
Uncertain significance
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607408.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.1046
Observation 2:
Comment on evidence:
Heterologous cells (CHO), FACS assays
Result:
Normal cell surface LDLR, LDL-LDLR binding and uptake
|
|
|
Likely benign
(Apr 05, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000730501.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
|
|
|
Likely benign
(May 12, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemias
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000903098.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
|
|
|
Likely benign
(Aug 31, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697241.2
First in ClinVar: Feb 28, 2015 Last updated: Sep 14, 2020 |
Comment:
Variant summary: LDLR c.58G>A (p.Gly20Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: LDLR c.58G>A (p.Gly20Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 255636 control chromosomes, predominantly at a frequency of 0.0024 within the Ashkenazi Jewish subpopulation in the gnomAD database. This frequency is approximately 2-fold the estimated maximum allele frequency expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.58G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia, however without evidence for co-segrgation with disease. In a family with Familial Hypercholesterolemia (FH), 1 transmission of the variant allele and 1 transmission of the reference allele to affected individuals was reported (Medeiros_2014). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants in LDLR have also been reported in FH patients in the literature (examples- Tejedor_2011, Komarova_2013, Klancar_2015), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function, showing no damaging effects by this variant (examples- Thormaehlen_2015, Pavlouskova_2016). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=5; uncertain significance, n=4). Based on the evidence outlined above, the variant was classified as likely benign. (less)
|
|
|
Likely benign
(Feb 12, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV001433283.1
First in ClinVar: Sep 24, 2020 Last updated: Sep 24, 2020 |
|
|
|
Benign
(Jan 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440726.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
|
|
|
Benign
(May 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002047182.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
|
|
|
Benign
(Apr 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004562294.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
|
|
|
Likely benign
(May 22, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002653247.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Benign
(Dec 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
GENinCode PLC
Accession: SCV005074000.1
First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 |
|
|
|
Benign
(Jul 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004011015.12
First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024 |
Comment:
LDLR: BS3:Supporting, BS1, BS2
Number of individuals with the variant: 3
|
|
|
Likely benign
(Jun 02, 2024)
|
no assertion criteria provided
Method: clinical testing
|
LDLR-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004773397.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
|
|
|
Uncertain significance
(Nov 29, 2010)
|
no assertion criteria provided
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Accession: SCV000268533.1
First in ClinVar: May 21, 2016 Last updated: May 21, 2016 |
Number of individuals with the variant: 2
|
|
|
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: SCV000605999.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
|
Likely benign
(Jan 08, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001463950.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
not provided
(-)
|
no classification provided
(in vitro)
Method: in vitro
|
not provided
Affected status: not applicable
Allele origin:
not applicable
|
Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Accession: SCV000189524.1
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
|
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
0/190 non-FH alleles; 0/150 normolipidemic chromosomes
Comment:
A functional analysis was previously published (Pavloušková et al, 2016). This variant has no effect on LDLR protein function.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Comment:
MAF =<0.3%. "Little/No effect" on the LDL receptor activity based on experimental validation.
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Comment:
Variant summary: LDLR c.58G>A (p.Gly20Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 255636 control chromosomes, predominantly at a frequency of 0.0024 within the Ashkenazi Jewish subpopulation in the gnomAD database. This frequency is approximately 2-fold the estimated maximum allele frequency expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.58G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia, however without evidence for co-segrgation with disease. In a family with Familial Hypercholesterolemia (FH), 1 transmission of the variant allele and 1 transmission of the reference allele to affected individuals was reported (Medeiros_2014). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants in LDLR have also been reported in FH patients in the literature (examples- Tejedor_2011, Komarova_2013, Klancar_2015), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function, showing no damaging effects by this variant (examples- Thormaehlen_2015, Pavlouskova_2016). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=5; uncertain significance, n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
LDLR: BS3:Supporting, BS1, BS2
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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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no known functional consequence
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Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Accession: SCV000189524.1
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Comment:
non-disruptive missense
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Comment:
The NM_000527.5(LDLR):c.58G>A (p.Gly20Arg) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BS3, BS4 and PP1_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BS2 - Variant identified in 5 unaffected relatives from Centre of molecular biology and gene therapy and 1 elderly heterozygous from the ABraOM database. BS3 - Level 1 assays: PMID 27175606: Heterologous cells (CHO), CLSM assays - result - normal cell surface LDLR, normal LDL-LDLR binding. ---- although not quantified, assume whole cycle is above 90% of wild-type, so BS3 is Met. BS4 - Variant does not segregate with FH phenotype in 8 informative meiosis from at least 3 families from different labs (Centre of molecular biology and gene therapy, University of British Columbia and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis from Centre of molecular biology and gene therapy. Variant has 3 strong evidence codes towards Benign, enough to classify as Benign, and only 1 moderate evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Benign.
Comment:
0/190 non-FH alleles; 0/150 normolipidemic chromosomes
Comment:
A functional analysis was previously published (Pavloušková et al, 2016). This variant has no effect on LDLR protein function.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Comment:
MAF =<0.3%. "Little/No effect" on the LDL receptor activity based on experimental validation.
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Comment:
Variant summary: LDLR c.58G>A (p.Gly20Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 255636 control chromosomes, predominantly at a frequency of 0.0024 within the Ashkenazi Jewish subpopulation in the gnomAD database. This frequency is approximately 2-fold the estimated maximum allele frequency expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.58G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia, however without evidence for co-segrgation with disease. In a family with Familial Hypercholesterolemia (FH), 1 transmission of the variant allele and 1 transmission of the reference allele to affected individuals was reported (Medeiros_2014). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants in LDLR have also been reported in FH patients in the literature (examples- Tejedor_2011, Komarova_2013, Klancar_2015), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function, showing no damaging effects by this variant (examples- Thormaehlen_2015, Pavlouskova_2016). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=5; uncertain significance, n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
LDLR: BS3:Supporting, BS1, BS2
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Variability in assigning pathogenicity to incidental findings: insights from LDLR sequence linked to the electronic health record in 1013 individuals. | Safarova MS | European journal of human genetics : EJHG | 2017 | PMID: 28145427 |
| The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey. | Gabčová D | Physiological research | 2017 | PMID: 27824480 |
| Homozygous Familial Hypercholesterolemia in Spain: Prevalence and Phenotype-Genotype Relationship. | Sánchez-Hernández RM | Circulation. Cardiovascular genetics | 2016 | PMID: 27784735 |
| Functional analysis of the p.(Leu15Pro) and p.(Gly20Arg) sequence changes in the signal sequence of LDL receptor. | Pavloušková J | Atherosclerosis | 2016 | PMID: 27175606 |
| Mutational analysis of a cohort with clinical diagnosis of familial hypercholesterolemia: considerations for genetic diagnosis improvement. | Medeiros AM | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26020417 |
| Next-generation-sequencing-based identification of familial hypercholesterolemia-related mutations in subjects with increased LDL-C levels in a latvian population. | Radovica-Spalvina I | BMC medical genetics | 2015 | PMID: 26415676 |
| Universal Screening for Familial Hypercholesterolemia in Children. | Klančar G | Journal of the American College of Cardiology | 2015 | PMID: 26361156 |
| Contribution of mutations in low density lipoprotein receptor (LDLR) and lipoprotein lipase (LPL) genes to familial combined hyperlipidemia (FCHL): a reappraisal by using a resequencing approach. | Minicocci I | Atherosclerosis | 2015 | PMID: 26342331 |
| Correction: systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction. | PLOS Genetics Staff | PLoS genetics | 2015 | PMID: 25781017 |
| 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 |
| Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
| Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. | Do R | Nature | 2015 | PMID: 25487149 |
| Cardiovascular risk assessment of dyslipidemic children: analysis of biomarkers to identify monogenic dyslipidemia. | Medeiros AM | Journal of lipid research | 2014 | PMID: 24627126 |
| Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. | Lange LA | American journal of human genetics | 2014 | PMID: 24507775 |
| Familial hypercholesterolemia mutations in Petrozavodsk: no similarity to St. Petersburg mutation spectrum. | Komarova TY | BMC medical genetics | 2013 | PMID: 24373485 |
| Actionable, pathogenic incidental findings in 1,000 participants' exomes. | Dorschner MO | American journal of human genetics | 2013 | PMID: 24055113 |
| Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
| Mutation detection in Croatian patients with familial hypercholesterolemia. | Pećin I | Annals of human genetics | 2013 | PMID: 23130880 |
| Pooled DNA resequencing of 68 myocardial infarction candidate genes in French canadians. | Beaudoin M | Circulation. Cardiovascular genetics | 2012 | PMID: 22923420 |
| Genetic analysis of familial hypercholesterolaemia in Western Australia. | Hooper AJ | Atherosclerosis | 2012 | PMID: 22883975 |
| The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. | Tichý L | Atherosclerosis | 2012 | PMID: 22698793 |
| New contributions to the study of common double mutants in the human LDL receptor gene. | Tejedor MT | Die Naturwissenschaften | 2011 | PMID: 21935675 |
| 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 |
| Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform. | Alonso R | Clinical biochemistry | 2009 | PMID: 19318025 |
| Diagnosis of families with familial hypercholesterolaemia and/or Apo B-100 defect by means of DNA analysis of LDL-receptor gene mutations. | Widhalm K | Journal of inherited metabolic disease | 2007 | PMID: 17347910 |
| Update of the molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human mutation | 2005 | PMID: 16250003 |
| The molecular basis of familial hypercholesterolaemia in Turkish patients. | Sözen MM | Atherosclerosis | 2005 | PMID: 15823276 |
| Genetic screening of patients with familial hypercholesterolaemia (FH): a New Zealand perspective. | Laurie AD | Atherosclerosis. Supplements | 2004 | PMID: 15556094 |
| Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia. | Amsellem S | Human genetics | 2002 | PMID: 12436241 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/be4b2a4c-4d4f-4372-99c1-a538940653d5 | - | - | - | - |
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Text-mined citations for rs147509697 ...
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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.