Disrupt SDE motif. SDE bind structural Ca2+.
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.681C>A (p.Asp227Glu)
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.
(6)
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.681C>A (p.Asp227Glu)
Variation ID: 403632 Accession: VCV000403632.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11216263 (GRCh37) [ NCBI UCSC ] 19: 11105587 (GRCh38) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 9, 2017 May 1, 2024 Nov 1, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.681C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Asp227Glu missense NM_001195798.2:c.681C>A NP_001182727.1:p.Asp227Glu missense NM_001195799.2:c.558C>A NP_001182728.1:p.Asp186Glu missense NM_001195800.2:c.314-1805C>A intron variant NM_001195803.2:c.314-978C>A intron variant NC_000019.10:g.11105587C>A NC_000019.9:g.11216263C>A NG_009060.1:g.21207C>A LRG_274:g.21207C>A LRG_274t1:c.681C>A LRG_274p1:p.Asp227Glu - Protein change
- D227E, D186E
- Other names
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- Canonical SPDI
- NC_000019.10:11105586:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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| 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. |
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| 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. |
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| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 26, 2022 | RCV000455843.5 | |
| Likely pathogenic (1) |
criteria provided, single submitter
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May 19, 2022 | RCV002248667.2 | |
| Pathogenic (1) |
criteria provided, single submitter
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May 26, 2021 | RCV002365580.2 | |
| Pathogenic (1) |
criteria provided, single submitter
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Nov 1, 2023 | RCV003581665.2 |
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. |
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Pathogenic
(Nov 05, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Additional submitter:
Centre of Molecular Biology and Gene Therapy, University Hospital Brno
Accession: SCV000540751.1
First in ClinVar: Apr 09, 2017 Last updated: Apr 09, 2017 |
Comment:
Disrupt SDE motif. SDE bind structural Ca2+.
Number of individuals with the variant: 1
Clinical Features:
Hypercholesterolemia (present)
Age: 16-58 years
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
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Likely pathogenic
(May 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002520220.2
First in ClinVar: May 28, 2022 Last updated: Mar 04, 2023 |
Comment:
Also known as p.D206E and FH-Afrikans; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant … (more)
Also known as p.D206E and FH-Afrikans; 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); This variant is associated with the following publications: (PMID: 11491306, 7682459, 27680772, 29128982, 28502495, 18718593, 31491741, 32331935, 17087781) (less)
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Pathogenic
(Oct 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003827806.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004298331.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 227 of the LDLR … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 227 of the LDLR protein (p.Asp227Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2352257, 2569482, 17087781, 17539906, 19467224, 21310417, 21382890, 22883975, 31491741). This variant is also known as Asp206Glu. ClinVar contains an entry for this variant (Variation ID: 403632). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002664174.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.D227E pathogenic mutation (also known as c.681C>A), located in coding exon 4 of the LDLR gene, results from a C to A substitution at … (more)
The p.D227E pathogenic mutation (also known as c.681C>A), located in coding exon 4 of the LDLR gene, results from a C to A substitution at nucleotide position 681. The aspartic acid at codon 227 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration, which is also known as p.D206E, has been reported in familial hypercholesterolemia (FH) cohorts in both the heterozygous and homozygous states (Charng MJ et al. Eur J Clin Invest, 2006 Dec;36:866-74; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Reiman A et al. Ann Clin Biochem, 2016 Nov;53:654-662; Hori M et al. Atherosclerosis, 2019 10;289:101-108). In addition, a different alteration located at the same position, resulting in the same protein change, c.681C>G (p.D227E), is a founder mutation that accounts for the majority of FH in the Afrikaner population (Leitersdorf et al. J Clin Invest.1989;84(3):954-61; King et al. N Z Med J. 2010;123(1319):79-82) and had also been reported in affected individuals of multiple ethnicities (Gudnason et al. Arterioscler. Thromb. 1993;13(1):56-63; Leren et al. Semin Vasc Med. 2004;4(1):75-85; Bertolini et al Atherosclerosis 2013;227(2):342-348; Sharifi et al. Metab. Clin. Exp. 2016;65(3):48-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606197.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Comment:
Comment:
Also known as p.D206E and FH-Afrikans; 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); This variant is associated with the following publications: (PMID: 11491306, 7682459, 27680772, 29128982, 28502495, 18718593, 31491741, 32331935, 17087781)
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 227 of the LDLR protein (p.Asp227Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2352257, 2569482, 17087781, 17539906, 19467224, 21310417, 21382890, 22883975, 31491741). This variant is also known as Asp206Glu. ClinVar contains an entry for this variant (Variation ID: 403632). 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%. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.D227E pathogenic mutation (also known as c.681C>A), located in coding exon 4 of the LDLR gene, results from a C to A substitution at nucleotide position 681. The aspartic acid at codon 227 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration, which is also known as p.D206E, has been reported in familial hypercholesterolemia (FH) cohorts in both the heterozygous and homozygous states (Charng MJ et al. Eur J Clin Invest, 2006 Dec;36:866-74; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Reiman A et al. Ann Clin Biochem, 2016 Nov;53:654-662; Hori M et al. Atherosclerosis, 2019 10;289:101-108). In addition, a different alteration located at the same position, resulting in the same protein change, c.681C>G (p.D227E), is a founder mutation that accounts for the majority of FH in the Afrikaner population (Leitersdorf et al. J Clin Invest.1989;84(3):954-61; King et al. N Z Med J. 2010;123(1319):79-82) and had also been reported in affected individuals of multiple ethnicities (Gudnason et al. Arterioscler. Thromb. 1993;13(1):56-63; Leren et al. Semin Vasc Med. 2004;4(1):75-85; Bertolini et al Atherosclerosis 2013;227(2):342-348; Sharifi et al. Metab. Clin. Exp. 2016;65(3):48-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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:
Disrupt SDE motif. SDE bind structural Ca2+.
Comment:
Also known as p.D206E and FH-Afrikans; 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); This variant is associated with the following publications: (PMID: 11491306, 7682459, 27680772, 29128982, 28502495, 18718593, 31491741, 32331935, 17087781)
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 227 of the LDLR protein (p.Asp227Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2352257, 2569482, 17087781, 17539906, 19467224, 21310417, 21382890, 22883975, 31491741). This variant is also known as Asp206Glu. ClinVar contains an entry for this variant (Variation ID: 403632). 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%. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.D227E pathogenic mutation (also known as c.681C>A), located in coding exon 4 of the LDLR gene, results from a C to A substitution at nucleotide position 681. The aspartic acid at codon 227 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration, which is also known as p.D206E, has been reported in familial hypercholesterolemia (FH) cohorts in both the heterozygous and homozygous states (Charng MJ et al. Eur J Clin Invest, 2006 Dec;36:866-74; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Reiman A et al. Ann Clin Biochem, 2016 Nov;53:654-662; Hori M et al. Atherosclerosis, 2019 10;289:101-108). In addition, a different alteration located at the same position, resulting in the same protein change, c.681C>G (p.D227E), is a founder mutation that accounts for the majority of FH in the Afrikaner population (Leitersdorf et al. J Clin Invest.1989;84(3):954-61; King et al. N Z Med J. 2010;123(1319):79-82) and had also been reported in affected individuals of multiple ethnicities (Gudnason et al. Arterioscler. Thromb. 1993;13(1):56-63; Leren et al. Semin Vasc Med. 2004;4(1):75-85; Bertolini et al Atherosclerosis 2013;227(2):342-348; Sharifi et al. Metab. Clin. Exp. 2016;65(3):48-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients. | Hori M | Atherosclerosis | 2019 | PMID: 31491741 |
| Double-heterozygous autosomal dominant hypercholesterolemia: Clinical characterization of an underreported disease. | Sjouke B | Journal of clinical lipidology | 2016 | PMID: 27919364 |
| Genetic diagnosis of familial hypercholesterolaemia using a rapid biochip array assay for 40 common LDLR, APOB and PCSK9 mutations. | Martin R | Atherosclerosis | 2016 | PMID: 27680772 |
| Pediatric experience with mipomersen as adjunctive therapy for homozygous familial hypercholesterolemia. | Raal FJ | Journal of clinical lipidology | 2016 | PMID: 27578117 |
| Molecular testing for familial hypercholesterolaemia-associated mutations in a UK-based cohort: development of an NGS-based method and comparison with multiplex polymerase chain reaction and oligonucleotide arrays. | Reiman A | Annals of clinical biochemistry | 2016 | PMID: 26748104 |
| 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 |
| 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 |
| An apparent inconsistency in parent to offspring transmission of point mutations of LDLR gene in familial hypercholesterolemia. | Rabacchi C | Clinica chimica acta; international journal of clinical chemistry | 2009 | PMID: 19467224 |
| Multiplex ARMS analysis to detect 13 common mutations in familial hypercholesterolaemia. | Taylor A | Clinical genetics | 2007 | PMID: 17539906 |
| Identification and characterization of novel low-density lipoprotein receptor mutations of familial hypercholesterolaemia patients in Taiwan. | Charng MJ | European journal of clinical investigation | 2006 | PMID: 17087781 |
| An exon 4 mutation identified in the majority of South African familial hypercholesterolaemics. | Kotze MJ | Journal of medical genetics | 1990 | PMID: 2352257 |
| Two common low density lipoprotein receptor gene mutations cause familial hypercholesterolemia in Afrikaners. | Leitersdorf E | The Journal of clinical investigation | 1989 | PMID: 2569482 |
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Text-mined citations for rs121908028 ...
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.