ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1966C>A (p.His656Asn)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.1966C>A (p.His656Asn)
Variation ID: 252136 Accession: VCV000252136.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11120212 (GRCh38) [ NCBI UCSC ] 19: 11230888 (GRCh37) [ 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 Jul 29, 2016 May 1, 2024 Jun 18, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.1966C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.His656Asn missense NM_001195798.2:c.1966C>A NP_001182727.1:p.His656Asn missense NM_001195799.2:c.1843C>A NP_001182728.1:p.His615Asn missense NM_001195800.2:c.1462C>A NP_001182729.1:p.His488Asn missense NM_001195803.2:c.1585C>A NP_001182732.1:p.His529Asn missense NC_000019.10:g.11120212C>A NC_000019.9:g.11230888C>A NG_009060.1:g.35832C>A LRG_274:g.35832C>A LRG_274t1:c.1966C>A LRG_274p1:p.His656Asn - Protein change
- H656N, H488N, H615N, H529N
- Other names
- NM_000527.5(LDLR):c.1966C>A
- Canonical SPDI
- NC_000019.10:11120211: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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
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
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
4059 | 4334 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Uncertain significance (8) |
reviewed by expert panel
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Jun 18, 2021 | RCV000237688.12 | |
Likely pathogenic (1) |
no assertion criteria provided
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Aug 16, 2016 | RCV000786344.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 13, 2016 | RCV002418057.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 24, 2023 | RCV001242724.7 |
Submissions - Germline
Classification
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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
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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
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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
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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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Uncertain significance
(Jun 18, 2021)
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reviewed by expert panel
Method: curation
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Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV001960935.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Comment:
NM_000527.5(LDLR):c.1966C>A (p.His656Asn) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (BS3, PP1_Strong, PM2, PP3 and PP4) as defined … (more)
NM_000527.5(LDLR):c.1966C>A (p.His656Asn) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (BS3, PP1_Strong, PM2, PP3 and PP4) 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: BS3 - PMID: 32015373 - Level 1 assay - study on heterologous cells (CHO-ldlA7), Western blot and FACS assays - results - Normal (95%) cell surface LDLR, LDL-LDLR binding (100%) and uptake (90-95%). ---- functional study is consistent with no damaging effect. PP1_strong - 1 family with 6 informative meiosis is reported by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PM2 - PopMax MAF = 0.00002638 (0.0026%) in European non-Finnish exomes (gnomAD v2.1.1). PP3 - REVEL: 0,905. PP4 - Variant meets PM2. Variant is reported in 1 index case fulfills Simon-Broome criteria. (less)
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Likely pathogenic
(Mar 25, 2016)
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criteria provided, single submitter
Method: literature only
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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LDLR-LOVD, British Heart Foundation
Accession: SCV000295782.2
First in ClinVar: Jul 29, 2016 Last updated: Sep 30, 2017 |
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
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Benign
(Mar 01, 2016)
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criteria provided, single submitter
Method: research
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Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
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Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000322993.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
0/200 non-FH alleles
Observation 1:
Comment on evidence:
%MAF (ExAC):0.001648
Observation 2:
Comment on evidence:
Heterologous cells (CHO), FACS assays
Result:
Normal cell surface LDLR, binding and uptake
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Likely pathogenic
(Dec 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503441.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subject mutated among 2600 FH index cases screened = 1 , family members = 5 with co-segregation / previously described in association with FH
Number of individuals with the variant: 1
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Benign
(Mar 01, 2016)
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criteria provided, single submitter
Method: research
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607659.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.001648
Observation 2:
Comment on evidence:
Heterologous cells (CHO), FACS assays
Result:
Normal cell surface LDLR, LDL-LDLR binding and uptake
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Uncertain significance
(Jul 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429019.1
First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Nov 24, 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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Invitae
Accession: SCV001415830.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 656 of the LDLR protein (p.His656Asn). … (more)
This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 656 of the LDLR protein (p.His656Asn). This variant is present in population databases (rs762815611, gnomAD 0.004%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 15241806, 15823288, 20828696, 21382890, 23375686). This variant is also known as H635N. ClinVar contains an entry for this variant (Variation ID: 252136). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.His656 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11737238), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain Significance
(Mar 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004824113.1
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)
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Comment:
This missense variant (also known as p.His635Asn in the mature protein) replaces histidine with asparagine at codon 656 of the LDLR protein. Computational prediction suggests … (more)
This missense variant (also known as p.His635Asn in the mature protein) replaces histidine with asparagine at codon 656 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant does not have a significant impact on LDLR binding activity (PMID: 32015373). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15241806, 15823288, 20828696, 23375686, 33418990). It has also been reported in individuals with suspected familial hypercholesterolemia (PMID: 21382890, 33955087). This variant has been identified in 3/251440 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient 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: 1
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Likely pathogenic
(May 13, 2016)
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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: SCV002718911.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.H656N variant (also known as c.1966C>A), located in coding exon 13 of the LDLR gene, results from a C to A substitution at nucleotide … (more)
The p.H656N variant (also known as c.1966C>A), located in coding exon 13 of the LDLR gene, results from a C to A substitution at nucleotide position 1966. The histidine at codon 656 is replaced by asparagine, an amino acid with similar properties, and is located in the EGF precursor-like domain. This variant, also referred to as p.H635N, has been reported in unrelated individuals reported to have familial hypercholesterolemia (Mozas P et al. Hum Mutat. 2004:24(2):187; Damgaard D et al. Atherosclerosis. 2005;180(1):155-60; van der Graaf A et al. Circulation. 2011;123(11):1167-73; Bertolini S et al. Atherosclerosis. 2013;227(2):342-8). This variant was also reported in a myocardial infarction-free control group, though clinical details were limited (Do R et al. Nature. 2015;518(7537):102-6). A study using surface plasmon resonance spectroscopy showed that this variant results in altered binding for substrate at low pH (Lo Surdo P et al. EMBO Rep. 2011;12(12):1300-5). In addition, another alteration affecting this amino acid (p.H656Q, c.1968C>G) has been reported in association with hypercholesterolemia (Descamps OS et al. Eur J Clin Invest. 2001;31(11):958-65 (reported as p.H635Q)). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. Based on data from ExAC, the A allele has an overall frequency of <0.01% (2/106164). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (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: SCV000606564.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Likely pathogenic
(Aug 16, 2016)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000925122.1
First in ClinVar: Jun 30, 2019 Last updated: Jun 30, 2019 |
Comment:
The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB and PCSK9. … (more)
The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB and PCSK9. Results showed that the following variant was identified: p.His656Asn (c.1966C>A) in the LDLR gene (NM_000527.4) The lab classifies this variant as likely pathogenic. Given sufficient case data and functional studies, we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least five unrelated cases of familial hypercholesterolemia (not including this patient's family). There is strong case data. Mozas P et al. Hum Mutat. 2004:24(2):187, reported this variant in one individual and predicted that the basic to neurtral amino acid change could be expected to alter the conformation of the protein and, therefore, to prevent the transport to the Golgi apparatus of the misfolded LDLR. This article reports the variant as p.H635N Damgaard D et al. Atherosclerosis. 2005;180(1):155-60 reported this variant as novel in two individuals of a large FH cohort. They did not provide additional phenotype details. This article reports the variant as p.H635N van der Graaf A et al. Circulation. 2011;123(11):1167-73 reported this variant in a pediatric individual who presented with familial hypercholesterolemia. They did not provide additional phenotypic details. Bertolini et al. Atherosclerosis. 2013 Apr;227(2):342-8 reported this variant in their cohort of FH patients, but supplemental figures are unavailable. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging. The histadine at codon 656 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at the same codon (p.H635Q). A study using surface plasmon resonance spectroscopy showed that this variant results in altered binding for substrate at low pH (Lo Surdo P et al. EMBO Rep. 2011;12(12):1300-5). In addition, another alteration affecting this amino acid (p.H656Q, c.1968C>G) has been reported in association with hypercholesterolemia (Descamps OS et al. Eur J Clin Invest. 2001;31(11):958-65 (reported as p.H635Q)). There are two individuals with variation at codon 656 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of August 16, 2016). (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Founder effects facilitate the use of a genotyping-based approach to molecular diagnosis in Swedish patients with familial hypercholesterolaemia. | Benedek P | Journal of internal medicine | 2021 | PMID: 33955087 |
The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia. | Meshkov A | Genes | 2021 | PMID: 33418990 |
Population genetic screening efficiently identifies carriers of autosomal dominant diseases. | Grzymski JJ | Nature medicine | 2020 | PMID: 32719484 |
Mutation type classification and pathogenicity assignment of sixteen missense variants located in the EGF-precursor homology domain of the LDLR. | Galicia-Garcia U | Scientific reports | 2020 | PMID: 32015373 |
Identification of roles for H264, H306, H439, and H635 in acid-dependent lipoprotein release by the LDL receptor. | Dong H | Journal of lipid research | 2017 | PMID: 27895090 |
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH. | Lo Surdo P | EMBO reports | 2011 | PMID: 22081141 |
Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children. | van der Graaf A | Circulation | 2011 | PMID: 21382890 |
Update of the Portuguese Familial Hypercholesterolaemia Study. | Medeiros AM | Atherosclerosis | 2010 | PMID: 20828696 |
The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population. | Damgaard D | Atherosclerosis | 2005 | PMID: 15823288 |
Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR. | Mozas P | Human mutation | 2004 | PMID: 15241806 |
Impact of genetic defects on atherosclerosis in patients suspected of familial hypercholesterolaemia. | Descamps OS | European journal of clinical investigation | 2001 | PMID: 11737238 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/29ba2878-e776-400d-a89d-3ebaa40d7543 | - | - | - | - |
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Text-mined citations for rs762815611 ...
HelpRecord last updated Sep 01, 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.