ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1381G>A (p.Gly461Ser)
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.
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(4); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.1381G>A (p.Gly461Ser)
Variation ID: 36456 Accession: VCV000036456.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11113557 (GRCh38) [ NCBI UCSC ] 19: 11224233 (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 Apr 4, 2013 Jun 24, 2023 May 4, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.1381G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Gly461Ser missense NM_000527.4(LDLR):c.1381G>A NM_001195798.2:c.1381G>A NP_001182727.1:p.Gly461Ser missense NM_001195799.2:c.1258G>A NP_001182728.1:p.Gly420Ser missense NM_001195800.2:c.877G>A NP_001182729.1:p.Gly293Ser missense NM_001195803.2:c.1000G>A NP_001182732.1:p.Gly334Ser missense NC_000019.10:g.11113557G>A NC_000019.9:g.11224233G>A NG_009060.1:g.29177G>A LRG_274:g.29177G>A LRG_274t1:c.1381G>A LRG_274p1:p.Gly461Ser - Protein change
- G461S, G420S, G293S, G334S
- Other names
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- Canonical SPDI
- NC_000019.10:11113556: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.
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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) 0.00001
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 |
4064 | 4339 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2020 | RCV000030128.7 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Aug 28, 2021 | RCV001050334.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 4, 2023 | RCV003234927.1 |
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
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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
(Oct 19, 2017)
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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: SCV001429519.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
Number of individuals with the variant: 1
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Uncertain significance
(Aug 28, 2021)
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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: SCV001214433.2
First in ClinVar: Apr 15, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glycine with serine at codon 461 of the LDLR protein (p.Gly461Ser). The glycine residue is weakly conserved and there is a … (more)
This sequence change replaces glycine with serine at codon 461 of the LDLR protein (p.Gly461Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs193922568, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 36456). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; 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. 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)
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Uncertain significance
(May 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052783.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 24, 2023 |
Comment:
Variant summary: LDLR c.1381G>A (p.Gly461Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: LDLR c.1381G>A (p.Gly461Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250880 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1381G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Rimbert_2021, Tada_2022, Hou_2020, Trinder_2020). These data are currently insuffient to allow any conclusion about variant significance. 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: 31980526, 35047021, 36229376, 33079599). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as Likely Benign (n=1) and VUS (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Likely benign
(May 20, 2019)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001353773.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
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Uncertain significance
(Jan 29, 2020)
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criteria provided, single submitter
Method: curation
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Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001423096.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 02, 2022 |
Comment:
The p.Gly461Ser variant in LDLR has been reported in at least one individual with Familial Hypercholesterolemia in ClinVar (Variation ID: 36456), and has been identified … (more)
The p.Gly461Ser variant in LDLR has been reported in at least one individual with Familial Hypercholesterolemia in ClinVar (Variation ID: 36456), and has been identified in 0.003266% (1/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922568). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 36456). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. One VUS at the same position, p.Gly461Cys, has been reported in association with disease in ClinVar (Variation ID: 183113). This variant may be in a functional domain involved in cell signaling (PMID: 23815734, 16465405). In summary, the clinical significance of the p.Gly461Ser variant is uncertain. ACMG/AMP Criteria applied: PM1_Supporting, PM2, BP4 (Richards 2015). (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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Impact of variants of uncertain significance of LDL receptor on phenotypes of familial hypercholesterolemia. | Tada H | Journal of clinical lipidology | 2022 | PMID: 36229376 |
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 |
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 |
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
Novel LDLR variants in patients with familial hypercholesterolemia: in silico analysis as a tool to predict pathogenic variants in children and their families. | Mollaki V | Annals of human genetics | 2013 | PMID: 23815734 |
Six novel mutations of the LDL receptor gene in FH kindred of Sicilian and Paraguayan descent. | Cefalù AB | International journal of molecular medicine | 2006 | PMID: 16465405 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4008a92c-27a3-437c-9225-bd1f257054ed | - | - | - | - |
Text-mined citations for rs193922568 ...
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.