MAF =<0.3%, likely pathogenic based on the integrative in-silico score; LDL-C >=160 mg/dL
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.508G>A (p.Asp170Asn)
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.
Uncertain significance
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.508G>A (p.Asp170Asn)
Variation ID: 224617 Accession: VCV000224617.11
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11105414 (GRCh38) [ NCBI UCSC ] 19: 11216090 (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 May 21, 2016 Jul 7, 2024 Mar 25, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.508G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Asp170Asn missense NM_001195798.2:c.508G>A NP_001182727.1:p.Asp170Asn missense NM_001195799.2:c.385G>A NP_001182728.1:p.Asp129Asn missense NM_001195800.2:c.314-1978G>A intron variant NM_001195803.2:c.314-1151G>A intron variant NC_000019.10:g.11105414G>A NC_000019.9:g.11216090G>A NG_009060.1:g.21034G>A LRG_274:g.21034G>A LRG_274t1:c.508G>A LRG_274p1:p.Asp170Asn - Protein change
- D170N, D129N
- Other names
- -
- Canonical SPDI
- NC_000019.10:11105413:G: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4085 | 4361 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 13, 2023 | RCV000211593.11 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 22, 2023 | RCV001190232.4 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 25, 2024 | RCV004526645.2 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Aug 31, 2016)
|
criteria provided, single submitter
Method: research
|
Hypercholesterolemia, familial, 1
Moderate hypercholesterolemia
Affected status: no
Allele origin:
germline
|
Cardiovascular Biomarker Research Laboratory, Mayo Clinic
Study: RIGHT
Accession: SCV000266315.2 First in ClinVar: Mar 24, 2016 Last updated: Jun 20, 2017 |
Comment:
MAF =<0.3%, likely pathogenic based on the integrative in-silico score; LDL-C >=160 mg/dL
Indication for testing: Familial hypercholesterolemia
Age: 60-69 years
Sex: male
Ethnicity/Population group: White
Geographic origin: United States
|
|
|
Uncertain significance
(Mar 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001357679.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant (also known as p.Asp149Asn in the mature protein) replaces aspartic acid with asparagine at codon 170 of the LDLR protein. Computational prediction … (more)
This missense variant (also known as p.Asp149Asn in the mature protein) replaces aspartic acid with asparagine at codon 170 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 28145427). This variant has been identified in 3/251270 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)
|
|
|
Uncertain Significance
(Dec 13, 2023)
|
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: SCV004820174.1
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.Asp149Asn in the mature protein) replaces aspartic acid with asparagine at codon 170 of the LDLR protein. Computational prediction … (more)
This missense variant (also known as p.Asp149Asn in the mature protein) replaces aspartic acid with asparagine at codon 170 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 3/251270 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: 4
|
|
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Uncertain significance
(Mar 25, 2024)
|
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: SCV005039161.2
First in ClinVar: May 07, 2024 Last updated: Jul 07, 2024 |
Comment:
Variant summary: LDLR c.508G>A (p.Asp170Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: LDLR c.508G>A (p.Asp170Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251270 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.508G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia without evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36752612, 28145427, 33079599). ClinVar contains an entry for this variant (Variation ID: 224617). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
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Uncertain significance
(Oct 07, 2011)
|
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: SCV000268567.1
First in ClinVar: May 21, 2016 Last updated: May 21, 2016 |
Number of individuals with the variant: 1
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606140.1
First in ClinVar: Jun 20, 2017 Last updated: Jun 20, 2017 |
|
Comment:
Comment:
This missense variant (also known as p.Asp149Asn in the mature protein) replaces aspartic acid with asparagine at codon 170 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 28145427). This variant has been identified in 3/251270 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.
Comment:
This missense variant (also known as p.Asp149Asn in the mature protein) replaces aspartic acid with asparagine at codon 170 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 3/251270 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.
Comment:
Variant summary: LDLR c.508G>A (p.Asp170Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251270 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.508G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia without evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36752612, 28145427, 33079599). ClinVar contains an entry for this variant (Variation ID: 224617). Based on the evidence outlined above, the variant was classified as uncertain significance.
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:
MAF =<0.3%, likely pathogenic based on the integrative in-silico score; LDL-C >=160 mg/dL
Comment:
This missense variant (also known as p.Asp149Asn in the mature protein) replaces aspartic acid with asparagine at codon 170 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 28145427). This variant has been identified in 3/251270 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.
Comment:
This missense variant (also known as p.Asp149Asn in the mature protein) replaces aspartic acid with asparagine at codon 170 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 3/251270 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.
Comment:
Variant summary: LDLR c.508G>A (p.Asp170Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251270 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.508G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia without evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36752612, 28145427, 33079599). ClinVar contains an entry for this variant (Variation ID: 224617). Based on the evidence outlined above, the variant was classified as uncertain significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genotype-phenotype correlation in a large cohort of pediatric patients with heterozygous and homozygous familial hypercholesterolemia. | Reijman MD | Current opinion in lipidology | 2023 | PMID: 36752612 |
| Polygenic Contribution to Low-Density Lipoprotein Cholesterol Levels and Cardiovascular Risk in Monogenic Familial Hypercholesterolemia. | Trinder M | Circulation. Genomic and precision medicine | 2020 | PMID: 33079599 |
| 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 |
Text-mined citations for rs139089530 ...
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 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.