VCV000369849.17 - ClinVar

NM_000527.5(LDLR):c.2167G>T (p.Glu723Ter)

Germline

Classification

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.

(10)

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

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.2167G>T (p.Glu723Ter)

Variation ID: 369849 Accession: VCV000369849.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11123200 (GRCh38) [ NCBI UCSC ] 19: 11233876 (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	Dec 18, 2016	Nov 17, 2024	Oct 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.2167G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Glu723Ter	nonsense
NM_001195798.2:c.2167G>T	NP_001182727.1:p.Glu723Ter	nonsense
NM_001195799.2:c.2044G>T	NP_001182728.1:p.Glu682Ter	nonsense
NM_001195800.2:c.1663G>T	NP_001182729.1:p.Glu555Ter	nonsense
NM_001195803.2:c.1633G>T	NP_001182732.1:p.Glu545Ter	nonsense
NC_000019.10:g.11123200G>T
NC_000019.9:g.11233876G>T
NG_009060.1:g.38820G>T
LRG_274:g.38820G>T
LRG_274t1:c.2167G>T	LRG_274p1:p.E723*
LRG_274t1:c.2167G>T	LRG_274p1:p.Glu723Ter
	NP_000518.1:p.E723*

... more HGVS ... less HGVS

Protein change

E545*, E555*, E682*, E723*

Other names

Canonical SPDI

NC_000019.10:11123199:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA10654855 dbSNP: rs1057516127 VarSome

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
Gene	OMIM	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.
Hypercholesterolemia, familial, 1	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Oct 8, 2024	RCV000408760.6
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 14, 2019	RCV001256966.7
Familial hypercholesterolemia	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 6, 2023	RCV001389808.5
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Jul 27, 2023	RCV003372695.2
LDLR-related disorder	Pathogenic (1)	criteria provided, single submitter	Sep 23, 2023	RCV003401380.4

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.
Likely pathogenic (-)	criteria provided, single submitter (Wang et al. (Arterioscler Thromb Vasc Biol. 2016)) Method: clinical testing	Hypercholesterolemia, familial, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Robarts Research Institute, Western University Accession: SCV000484749.1 First in ClinVar: Dec 18, 2016 Last updated: Dec 18, 2016	Number of individuals with the variant: 1
Likely pathogenic (Dec 16, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV000503471.1 First in ClinVar: Dec 18, 2016 Last updated: Dec 18, 2016	Comment: subjects mutated among 2600 FH index cases screened = 5 , family members = 3/previously described in association with FH Number of individuals with the variant: 5
Pathogenic (Mar 30, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Hypercholesterolemia Affected status: yes Allele origin: germline	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille Accession: SCV000583932.1 First in ClinVar: Dec 18, 2016 Last updated: Dec 18, 2016 Comment: ACMG Guidelines: Pathogenic (i)	Number of individuals with the variant: 8 Clinical Features: Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present) Indication for testing: Familial Hypercholesterolemia Sex: mixed Geographic origin: France Comment on evidence: Dutch Lipid Clinic Scoring : Definite FH Secondary finding: no
Pathogenic (Mar 04, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV001433506.1 First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020
Pathogenic (Oct 14, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001715498.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Publications: PubMed (3) PubMed: 26802169‚ 28964736‚ 30586733 Comment: PVS1, PS4_moderate Number of individuals with the variant: 1
Pathogenic (Sep 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	LDLR-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004103123.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The LDLR c.2167G>T variant is predicted to result in premature protein termination (p.Glu723). This variant also described using legacy nomenclature as p.Glu702, has been documented … (more) The LDLR c.2167G>T variant is predicted to result in premature protein termination (p.Glu723). This variant also described using legacy nomenclature as p.Glu702, has been documented as a causative variant for Hypercholesterolemia (Wintjens et al. 2016. PubMed ID: 26802169; Defesche et al. 2017. PubMed ID: 28964736). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11233876-G-T). Nonsense variants in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Mar 03, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001591289.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 26802169‚ 28964736‚ 30586733‚ 20809525‚ 28645073 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 369849). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 369849). This premature translational stop signal has been observed in individual(s) with early-onset myocardial infarction and/or familial hypercholesterolemia (PMID: 26802169, 28964736, 30586733). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Glu723*) 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). (less)
Pathogenic (Jul 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV004359061.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 10428988‚ 26802169‚ 27765764‚ 28964736‚ 30586733‚ 31993549 Comment: This variant changes 1 nucleotide in exon 15 in the O-linked oligo-saccharide domain of the LDLR gene, creating a premature translation stop signal. This variant … (more) This variant changes 1 nucleotide in exon 15 in the O-linked oligo-saccharide domain of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 10428988, 26802169, 27765764, 28964736, 31993549). It has also been reported in an individual affected with early-onset myocardial infarction (PMID: 30586733). This variant has been identified in 1/31336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Jul 27, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004087569.2 First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 10428988‚ 26802169‚ 27765764‚ 28964736‚ 31993549 Comment: The p.E723* pathogenic mutation (also known as c.2167G>T), located in coding exon 15 of the LDLR gene, results from a G to T substitution at … (more) The p.E723* pathogenic mutation (also known as c.2167G>T), located in coding exon 15 of the LDLR gene, results from a G to T substitution at nucleotide position 2167. This changes the amino acid from a glutamic acid to a stop codon within coding exon 15. This variant (also referred to as Glu702STOP) has been detected in several individuals with familial hypercholesterolemia (Frénais R et al. J Lipid Res, 1999 Aug;40:1506-11; Wang J et al. Arterioscler Thromb Vasc Biol, 2016 Dec;36:2439-2445; Wintjens R et al. J Lipid Res, 2016 Mar;57:482-91; Defesche JC et al. J Clin Lipidol, 2017 Sep;11:1338-1346.e7; Garg A et al. J Endocr Soc, 2020 Jan;4:bvz015). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Oct 08, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV005397140.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Clinical Features: Hypercholesterolemia (present) Sex: male

Comment:

The LDLR c.2167G>T variant is predicted to result in premature protein termination (p.Glu723*). This variant also described using legacy nomenclature as p.Glu702*, has been documented as a causative variant for Hypercholesterolemia (Wintjens et al. 2016. PubMed ID: 26802169; Defesche et al. 2017. PubMed ID: 28964736). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11233876-G-T). Nonsense variants in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 369849). This premature translational stop signal has been observed in individual(s) with early-onset myocardial infarction and/or familial hypercholesterolemia (PMID: 26802169, 28964736, 30586733). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Glu723*) 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).

Comment:

This variant changes 1 nucleotide in exon 15 in the O-linked oligo-saccharide domain of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 10428988, 26802169, 27765764, 28964736, 31993549). It has also been reported in an individual affected with early-onset myocardial infarction (PMID: 30586733). This variant has been identified in 1/31336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

The p.E723* pathogenic mutation (also known as c.2167G>T), located in coding exon 15 of the LDLR gene, results from a G to T substitution at nucleotide position 2167. This changes the amino acid from a glutamic acid to a stop codon within coding exon 15. This variant (also referred to as Glu702STOP) has been detected in several individuals with familial hypercholesterolemia (Frénais R et al. J Lipid Res, 1999 Aug;40:1506-11; Wang J et al. Arterioscler Thromb Vasc Biol, 2016 Dec;36:2439-2445; Wintjens R et al. J Lipid Res, 2016 Mar;57:482-91; Defesche JC et al. J Clin Lipidol, 2017 Sep;11:1338-1346.e7; Garg A et al. J Endocr Soc, 2020 Jan;4:bvz015). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Molecular Characterization of Familial Hypercholesterolemia in a North American Cohort.	Garg A	Journal of the Endocrine Society	2019	PMID: 31993549
Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction.	Khera AV	Circulation	2019	PMID: 30586733
Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia.	Defesche JC	Journal of clinical lipidology	2017	PMID: 28964736
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
Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France.	Wintjens R	Journal of lipid research	2016	PMID: 26802169
Molecular spectrum of autosomal dominant hypercholesterolemia in France.	Marduel M	Human mutation	2010	PMID: 20809525
Apolipoprotein A-I kinetics in heterozygous familial hypercholesterolemia: a stable isotope study.	Frénais R	Journal of lipid research	1999	PMID: 10428988

Text-mined citations for rs1057516127 ...

These 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 Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_000527.5(LDLR):c.2167G>T (p.Glu723Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1057516127 ...