NM_000527.5(LDLR):c.2101G>A (p.Gly701Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PP1_Moderate and PP3) 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: PP1_moderate - Variant segregates with FH phenotype in 4 informative meioses in 2 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). PP3 - REVEL: 0,754.
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.2101G>A (p.Gly701Ser)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Uncertain significance
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.2101G>A (p.Gly701Ser)
Variation ID: 183130 Accession: VCV000183130.33
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11120483 (GRCh38) [ NCBI UCSC ] 19: 11231159 (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 May 1, 2024 Jun 18, 2021 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.2101G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Gly701Ser missense NM_001195798.2:c.2101G>A NP_001182727.1:p.Gly701Ser missense NM_001195799.2:c.1978G>A NP_001182728.1:p.Gly660Ser missense NM_001195800.2:c.1597G>A NP_001182729.1:p.Gly533Ser missense NM_001195803.2:c.1606+250G>A intron variant NC_000019.10:g.11120483G>A NC_000019.9:g.11231159G>A NG_009060.1:g.36103G>A LRG_274:g.36103G>A LRG_274t1:c.2101G>A LRG_274p1:p.Gly701Ser - Protein change
- G701S, G660S, G533S
- Other names
-
NM_000527.5(LDLR):c.2101G>A
- Canonical SPDI
- NC_000019.10:11120482:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
unknown functional consequenceunclear [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.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00009
Exome Aggregation Consortium (ExAC) 0.00012
The Genome Aggregation Database (gnomAD) 0.00012
- 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 |
4076 | 4352 | |
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. |
|---|---|---|---|---|
| Uncertain significance (3) |
criteria provided, single submitter
|
Jun 7, 2017 | RCV000162008.15 | |
| Uncertain significance (9) |
reviewed by expert panel
|
Jun 18, 2021 | RCV000238415.15 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 15, 2023 | RCV001181781.8 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jun 9, 2023 | RCV002415707.3 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Jun 18, 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: SCV001960939.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Comment:
NM_000527.5(LDLR):c.2101G>A (p.Gly701Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PP1_Moderate and PP3) as defined by the ClinGen … (more)
NM_000527.5(LDLR):c.2101G>A (p.Gly701Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PP1_Moderate and PP3) 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: PP1_moderate - Variant segregates with FH phenotype in 4 informative meioses in 2 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). PP3 - REVEL: 0,754. (less)
|
|
|
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: SCV000295875.2
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
Observation 3:
Number of individuals with the variant: 1
|
|
|
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: SCV000607677.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Comment on evidence:
%MAF(ExAC):0.01242
|
|
|
Uncertain significance
(Jun 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697222.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Variant summary: The LDLR c.2101G>A (p.Gly701Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging … (more)
Variant summary: The LDLR c.2101G>A (p.Gly701Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest has been found in a large and broad control population from ExAC in 17/137956 control chromosomes at a frequency of 0.0001232, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been reported in patients with hypercholesterolemia, coronary artery disease and/or myocardial infarction (Fouchier _2005, Duskova _2011, Thormaehlen_2015, Khera_2016) without strong evidence for causality. In two case-control studies, this variant was not significantly more enriched in patients with coronary artery disease and/or myocardial infarction than in controls (Thormaehlen_2015, Khera_2016). Based on LDLR uptake and complementation assay, one in vitro study has concluded that its pathogenicity or functional outcome is unclear (Thormaehlen _2015). There are conflicting reports of classification on this variant in ClinVar, likely pathogenic as well as likely benign (both in 2016). Taken together, this variant is currently classified as Variant of Unknown Significance. (less)
|
|
|
Uncertain Significance
(Jan 11, 2024)
|
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: SCV004818499.1
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 (also known as p.Gly680Ser in the mature protein) replaces glycine with serine at codon 701 of the LDLR protein. Computational prediction is … (more)
This missense variant (also known as p.Gly680Ser in the mature protein) replaces glycine with serine at codon 701 of the LDLR 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 shown this variant to cause a partial reduction in LDL uptake activity of the LDLR protein (PMID: 25647241). This variant has not shown significant association with increased LDL-C levels, coronary artery disease, or myocardial infarction (PMID: 22390909, 25647241). This variant has been identified in 25/282378 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is no indication that this variant is disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 19
|
|
|
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: SCV000540860.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Number of individuals with the variant: 2
Clinical Features:
Hypercholesterolemia (present)
Age: 46-58 years
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
|
|
|
Uncertain significance
(Oct 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002794037.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Uncertain significance
(Jul 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002943680.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 701 of the LDLR protein (p.Gly701Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 701 of the LDLR protein (p.Gly701Ser). This variant is present in population databases (rs368838866, gnomAD 0.04%). This missense change has been observed in individual(s) with hypercholesterolemia or referred for genetic testing (PMID: 16250003, 19007590, 19318025, 21310417, 22390909, 25487149). ClinVar contains an entry for this variant (Variation ID: 183130). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25647241). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Jun 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001140985.2
First in ClinVar: Jan 09, 2020 Last updated: Jun 03, 2023 |
|
|
|
Uncertain significance
(Mar 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001347005.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant (also known as p.Gly680Ser in the mature protein) replaces glycine with serine at codon 701 of the LDLR protein. Computational prediction is … (more)
This missense variant (also known as p.Gly680Ser in the mature protein) replaces glycine with serine at codon 701 of the LDLR 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 shown this variant to cause a partial reduction in LDL uptake activity of the LDLR protein (PMID: 25647241). This variant has not shown significant association with increased LDL-C levels, coronary artery disease, or myocardial infarction (PMID: 22390909, 25647241). This variant has been identified in 25/282378 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is no indication that this variant is disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Jun 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002724555.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.G701S variant (also known as c.2101G>A), located in coding exon 14 of the LDLR gene, results from a G to A substitution at nucleotide … (more)
The p.G701S variant (also known as c.2101G>A), located in coding exon 14 of the LDLR gene, results from a G to A substitution at nucleotide position 2101. The glycine at codon 701 is replaced by serine, an amino acid with similar properties. This variant has been detected in individuals from familial hypercholesterolemia, familial combined hyperlipidemia, and early onset myocardial infarction cohorts; however, in most cases clinical details were limited, and p.G701S was also seen in reportedly unaffected controls (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Civeira F et al. J. Am. Coll. Cardiol., 2008 Nov;52:1546-53; Dušková L et al. Atherosclerosis, 2011 May;216:139-45; Do R et al. Nature, 2015 Feb;518:102-6; Khera AV et al. J. Am. Coll. Cardiol., 2016 06;67:2578-89). The results of limited functional studies were inconclusive (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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: SCV000606599.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733828.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
|
|
Uncertain significance
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001461327.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001917981.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 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: SCV000189583.1
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:
Variant summary: The LDLR c.2101G>A (p.Gly701Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest has been found in a large and broad control population from ExAC in 17/137956 control chromosomes at a frequency of 0.0001232, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been reported in patients with hypercholesterolemia, coronary artery disease and/or myocardial infarction (Fouchier _2005, Duskova _2011, Thormaehlen_2015, Khera_2016) without strong evidence for causality. In two case-control studies, this variant was not significantly more enriched in patients with coronary artery disease and/or myocardial infarction than in controls (Thormaehlen_2015, Khera_2016). Based on LDLR uptake and complementation assay, one in vitro study has concluded that its pathogenicity or functional outcome is unclear (Thormaehlen _2015). There are conflicting reports of classification on this variant in ClinVar, likely pathogenic as well as likely benign (both in 2016). Taken together, this variant is currently classified as Variant of Unknown Significance.
Comment:
This missense variant (also known as p.Gly680Ser in the mature protein) replaces glycine with serine at codon 701 of the LDLR 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 shown this variant to cause a partial reduction in LDL uptake activity of the LDLR protein (PMID: 25647241). This variant has not shown significant association with increased LDL-C levels, coronary artery disease, or myocardial infarction (PMID: 22390909, 25647241). This variant has been identified in 25/282378 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is no indication that this variant is disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 701 of the LDLR protein (p.Gly701Ser). This variant is present in population databases (rs368838866, gnomAD 0.04%). This missense change has been observed in individual(s) with hypercholesterolemia or referred for genetic testing (PMID: 16250003, 19007590, 19318025, 21310417, 22390909, 25487149). ClinVar contains an entry for this variant (Variation ID: 183130). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25647241). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This missense variant (also known as p.Gly680Ser in the mature protein) replaces glycine with serine at codon 701 of the LDLR 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 shown this variant to cause a partial reduction in LDL uptake activity of the LDLR protein (PMID: 25647241). This variant has not shown significant association with increased LDL-C levels, coronary artery disease, or myocardial infarction (PMID: 22390909, 25647241). This variant has been identified in 25/282378 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is no indication that this variant is disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.G701S variant (also known as c.2101G>A), located in coding exon 14 of the LDLR gene, results from a G to A substitution at nucleotide position 2101. The glycine at codon 701 is replaced by serine, an amino acid with similar properties. This variant has been detected in individuals from familial hypercholesterolemia, familial combined hyperlipidemia, and early onset myocardial infarction cohorts; however, in most cases clinical details were limited, and p.G701S was also seen in reportedly unaffected controls (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Civeira F et al. J. Am. Coll. Cardiol., 2008 Nov;52:1546-53; Dušková L et al. Atherosclerosis, 2011 May;216:139-45; Do R et al. Nature, 2015 Feb;518:102-6; Khera AV et al. J. Am. Coll. Cardiol., 2016 06;67:2578-89). The results of limited functional studies were inconclusive (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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. |
|---|---|---|---|---|
|
unknown functional consequence
|
|
|
Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Accession: SCV000189583.1
|
Comment:
unclear
|
Comment:
NM_000527.5(LDLR):c.2101G>A (p.Gly701Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PP1_Moderate and PP3) 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: PP1_moderate - Variant segregates with FH phenotype in 4 informative meioses in 2 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). PP3 - REVEL: 0,754.
Comment:
Variant summary: The LDLR c.2101G>A (p.Gly701Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest has been found in a large and broad control population from ExAC in 17/137956 control chromosomes at a frequency of 0.0001232, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been reported in patients with hypercholesterolemia, coronary artery disease and/or myocardial infarction (Fouchier _2005, Duskova _2011, Thormaehlen_2015, Khera_2016) without strong evidence for causality. In two case-control studies, this variant was not significantly more enriched in patients with coronary artery disease and/or myocardial infarction than in controls (Thormaehlen_2015, Khera_2016). Based on LDLR uptake and complementation assay, one in vitro study has concluded that its pathogenicity or functional outcome is unclear (Thormaehlen _2015). There are conflicting reports of classification on this variant in ClinVar, likely pathogenic as well as likely benign (both in 2016). Taken together, this variant is currently classified as Variant of Unknown Significance.
Comment:
This missense variant (also known as p.Gly680Ser in the mature protein) replaces glycine with serine at codon 701 of the LDLR 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 shown this variant to cause a partial reduction in LDL uptake activity of the LDLR protein (PMID: 25647241). This variant has not shown significant association with increased LDL-C levels, coronary artery disease, or myocardial infarction (PMID: 22390909, 25647241). This variant has been identified in 25/282378 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is no indication that this variant is disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 701 of the LDLR protein (p.Gly701Ser). This variant is present in population databases (rs368838866, gnomAD 0.04%). This missense change has been observed in individual(s) with hypercholesterolemia or referred for genetic testing (PMID: 16250003, 19007590, 19318025, 21310417, 22390909, 25487149). ClinVar contains an entry for this variant (Variation ID: 183130). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25647241). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This missense variant (also known as p.Gly680Ser in the mature protein) replaces glycine with serine at codon 701 of the LDLR 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 shown this variant to cause a partial reduction in LDL uptake activity of the LDLR protein (PMID: 25647241). This variant has not shown significant association with increased LDL-C levels, coronary artery disease, or myocardial infarction (PMID: 22390909, 25647241). This variant has been identified in 25/282378 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is no indication that this variant is disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.G701S variant (also known as c.2101G>A), located in coding exon 14 of the LDLR gene, results from a G to A substitution at nucleotide position 2101. The glycine at codon 701 is replaced by serine, an amino acid with similar properties. This variant has been detected in individuals from familial hypercholesterolemia, familial combined hyperlipidemia, and early onset myocardial infarction cohorts; however, in most cases clinical details were limited, and p.G701S was also seen in reportedly unaffected controls (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Civeira F et al. J. Am. Coll. Cardiol., 2008 Nov;52:1546-53; Dušková L et al. Atherosclerosis, 2011 May;216:139-45; Do R et al. Nature, 2015 Feb;518:102-6; Khera AV et al. J. Am. Coll. Cardiol., 2016 06;67:2578-89). The results of limited functional studies were inconclusive (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Universal screening for familial hypercholesterolemia in 2 populations. | Sustar U | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 35913489 |
| Low Detection Rates of Genetic FH in Cohort of Patients With Severe Hypercholesterolemia in the United Arabic Emirates. | Rimbert A | Frontiers in genetics | 2022 | PMID: 35047021 |
| Lipoprotein(a) in hereditary hypercholesterolemia: Influence of the genetic cause, defective gene and type of mutation. | Marco-Benedí V | Atherosclerosis | 2022 | PMID: 34456049 |
| Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia. | Khera AV | Journal of the American College of Cardiology | 2016 | PMID: 27050191 |
| 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 |
| The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. | Tichý L | Atherosclerosis | 2012 | PMID: 22698793 |
| Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29,365 individuals tested for 64 specific low-density lipoprotein-receptor sequence variants. | Huijgen R | European heart journal | 2012 | PMID: 22390909 |
| An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia. | Dušková L | Atherosclerosis | 2011 | PMID: 21310417 |
| Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform. | Alonso R | Clinical biochemistry | 2009 | PMID: 19318025 |
| Frequency of low-density lipoprotein receptor gene mutations in patients with a clinical diagnosis of familial combined hyperlipidemia in a clinical setting. | Civeira F | Journal of the American College of Cardiology | 2008 | PMID: 19007590 |
| Update of the molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human mutation | 2005 | PMID: 16250003 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4ce3f966-2bbf-4b29-ad24-d066a9b9ef76 | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs368838866 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record 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.