ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.2215C>T (p.Gln739Ter)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.2215C>T (p.Gln739Ter)
Variation ID: 252258 Accession: VCV000252258.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11123248 (GRCh38) [ NCBI UCSC ] 19: 11233924 (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 Jul 29, 2016 May 1, 2024 Aug 29, 2022 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000527.5:c.2215C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Gln739Ter nonsense NM_001195798.2:c.2215C>T NP_001182727.1:p.Gln739Ter nonsense NM_001195799.2:c.2092C>T NP_001182728.1:p.Gln698Ter nonsense NM_001195800.2:c.1711C>T NP_001182729.1:p.Gln571Ter nonsense NM_001195803.2:c.1681C>T NP_001182732.1:p.Gln561Ter nonsense NC_000019.10:g.11123248C>T NC_000019.9:g.11233924C>T NG_009060.1:g.38868C>T LRG_274:g.38868C>T LRG_274t1:c.2215C>T LRG_274p1:p.Gln739Ter - Protein change
- Q739*, Q561*, Q571*, Q698*
- Other names
- NP_000518.1:p.Q739*
- NM_000527.5(LDLR):c.2215C>T
- p.Gln739Ter
- Canonical SPDI
- NC_000019.10:11123247:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
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 |
4042 | 4316 |
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. |
---|---|---|---|---|
Pathogenic (6) |
reviewed by expert panel
|
Aug 29, 2022 | RCV000237494.10 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 16, 2023 | RCV000791393.13 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jul 24, 2023 | RCV002418073.2 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jul 5, 2022 | RCV002509337.1 |
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
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. |
|
---|---|---|---|---|---|
Pathogenic
(Aug 29, 2022)
|
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: SCV002817128.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
The NM_000527.5(LDLR) :c.2215C>T (p.Gln739Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence code PVS1, PM2 and PP4 as defined by the ClinGen … (more)
The NM_000527.5(LDLR) :c.2215C>T (p.Gln739Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence code PVS1, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PVS1 - Stop in codon 739. It is upstream of amino acid 830. PP4 - Variant meets PM2 and is identified in one index case who fulfill FH/DLCN>=6 criteria for FH from Robarts Research Institute after alternative causes of high cholesterol were excluded. (less)
|
|
Pathogenic
(Mar 25, 2016)
|
criteria provided, single submitter
Method: literature only
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000295919.2
First in ClinVar: Jul 29, 2016 Last updated: Oct 10, 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
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Robarts Research Institute, Western University
Accession: SCV000484732.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Number of individuals with the variant: 2
|
|
Uncertain significance
(Dec 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503474.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subject mutated among 2600 FH index cases screened = 1/FH-Japan
Number of individuals with the variant: 1
|
|
Pathogenic
(Feb 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000544653.9
First in ClinVar: Apr 16, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln739*) in the LDLR gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln739*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 12417285, 20045108, 20538126, 21376320, 23375686). This variant is also known as p.Gln718X. ClinVar contains an entry for this variant (Variation ID: 252258). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Oct 29, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361871.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: LDLR c.2215C>T (p.Gln739X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: LDLR c.2215C>T (p.Gln739X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251316 control chromosomes (gnomAD). c.2215C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Yu_2002, Robles-Osorio_2006, Romano_2010, Chiou_2010, Pirillo_2017, Kolansky_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reported that the variant resulted in less than 2% of normal LDLR activity in patient derived skin fibroblasts (Kolansky_2008). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and as VUS (1x). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Jun 04, 2019)
|
criteria provided, single submitter
Method: research
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia
Accession: SCV001432561.1
First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
|
|
Pathogenic
(May 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II
Accession: SCV001653657.1
First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Geographic origin: Italy
|
|
Pathogenic
(Dec 14, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001356940.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This variant (also known as Q718X) changes 1 nucleotide in exon 15 of the LDLR gene, creating a premature translation stop signal. This variant is … (more)
This variant (also known as Q718X) changes 1 nucleotide in exon 15 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID:12417285, 20045108, 20538126, 21376320, 23375686). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. (less)
|
|
Pathogenic
(Jul 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002818622.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Also known as p.(Q718*); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated … (more)
Also known as p.(Q718*); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 32041611, 32331935, 32220565, 19026292, 28965616, 31491741, 33303402, 32423031, 23375686, 21376320, 20538126, 34037665, 20045108, 16314194, 12417285) (less)
|
|
Pathogenic
(Jul 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002724797.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.2215C>T (p.Q739*) alteration, located in exon 15 (coding exon 15) of the LDLR gene, consists of a C to T substitution at nucleotide position … (more)
The c.2215C>T (p.Q739*) alteration, located in exon 15 (coding exon 15) of the LDLR gene, consists of a C to T substitution at nucleotide position 2215. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 739. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in numerous individuals suspected to have familial hypercholesterolemia (FH) (Yu, 2002; Robles-Osorio, 2006; Kolansky, 2008; Chiou, 2010; Romano, 2010; Bertolini, 2013; Wang, 2016; Semenova, 2020; Tada, 2020; Di Taranto, 2021; Gill, 2021; Huang, 2022). Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
Pathogenic
(Jun 18, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002086866.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Genetic Analysis in a Taiwanese Cohort of 750 Index Patients with Clinically Diagnosed Familial Hypercholesterolemia. | Huang CC | Journal of atherosclerosis and thrombosis | 2022 | PMID: 33994402 |
Genetic spectrum of familial hypercholesterolemia and correlations with clinical expression: Implications for diagnosis improvement. | Di Taranto MD | Clinical genetics | 2021 | PMID: 34297352 |
Combined hyperlipidemia is genetically similar to isolated hypertriglyceridemia. | Gill PK | Journal of clinical lipidology | 2021 | PMID: 33303402 |
Verification of Underlying Genetic Cause in a Cohort of Russian Patients with Familial Hypercholesterolemia Using Targeted Next Generation Sequencing. | Semenova AE | Journal of cardiovascular development and disease | 2020 | PMID: 32423031 |
A catalog of the pathogenic mutations of LDL receptor gene in Japanese familial hypercholesterolemia. | Tada H | Journal of clinical lipidology | 2020 | PMID: 32331935 |
Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias. | Dron JS | BMC medical genomics | 2020 | PMID: 32041611 |
Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients. | Hori M | Atherosclerosis | 2019 | PMID: 31491741 |
Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study. | Pirillo A | Atherosclerosis. Supplements | 2017 | PMID: 28965616 |
Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically. | Wang J | Arteriosclerosis, thrombosis, and vascular biology | 2016 | PMID: 27765764 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
Array-based resequencing for mutations causing familial hypercholesterolemia. | Chiou KR | Atherosclerosis | 2011 | PMID: 21376320 |
Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
Detection of mutations and large rearrangements of the low-density lipoprotein receptor gene in Taiwanese patients with familial hypercholesterolemia. | Chiou KR | The American journal of cardiology | 2010 | PMID: 20538126 |
Identification and functional characterization of LDLR mutations in familial hypercholesterolemia patients from Southern Italy. | Romano M | Atherosclerosis | 2010 | PMID: 20045108 |
Longitudinal evaluation and assessment of cardiovascular disease in patients with homozygous familial hypercholesterolemia. | Kolansky DM | The American journal of cardiology | 2008 | PMID: 19026292 |
Genetic heterogeneity of autosomal dominant hypercholesterolemia in Mexico. | Robles-Osorio L | Archives of medical research | 2006 | PMID: 16314194 |
Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population. | Yu W | Atherosclerosis | 2002 | PMID: 12417285 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c4ca2e41-d963-4724-bc04-e9367a9c883c | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs370018159 ...
HelpRecord last updated Jun 23, 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.