VCV000251237.16 - ClinVar

NM_000527.5(LDLR):c.460C>T (p.Gln154Ter)

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.460C>T (p.Gln154Ter)

Variation ID: 251237 Accession: VCV000251237.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11105366 (GRCh38) [ NCBI UCSC ] 19: 11216042 (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	Sep 16, 2024	Apr 5, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.460C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Gln154Ter	nonsense
NM_001195798.2:c.460C>T	NP_001182727.1:p.Gln154Ter	nonsense
NM_001195799.2:c.337C>T	NP_001182728.1:p.Gln113Ter	nonsense
NM_001195800.2:c.314-2026C>T		intron variant
NM_001195803.2:c.314-1199C>T		intron variant
NC_000019.10:g.11105366C>T
NC_000019.9:g.11216042C>T
NG_009060.1:g.20986C>T
LRG_274:g.20986C>T
LRG_274t1:c.460C>T	LRG_274p1:p.Gln154Ter

... more HGVS ... less HGVS

Protein change

Q154*, Q113*

Other names

NP_000518.1:p.Q154*

Canonical SPDI

NC_000019.10:11105365:C: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.

Links

ClinGen: CA10584930 LDLR-LOVD, British Heart Foundation: LDLR_000060 dbSNP: rs879254534 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	4076	4352

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 (7)	criteria provided, multiple submitters, no conflicts	Mar 21, 2021	RCV000238392.10
Familial hypercholesterolemia	Pathogenic (1)	criteria provided, single submitter	Jul 8, 2021	RCV001060562.8
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Apr 5, 2023	RCV004020949.1
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 13, 2022	RCV004696889.1

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 (Mar 25, 2016)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: literature only	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	LDLR-LOVD, British Heart Foundation Accession: SCV000294724.2 First in ClinVar: Jul 29, 2016 Last updated: May 03, 2018	Publications: PubMed (4) PubMed: 10206683‚ 16542394‚ 17539906‚ 20145306 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
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: SCV000484744.1 First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016	Number of individuals with the variant: 1
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: SCV000503162.1 First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016	Comment: subject mutated among 2600 FH index cases screened = 1 Number of individuals with the variant: 1
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: SCV000583682.1 First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 Comment: ACMG Guidelines: Pathogenic (i)	Number of individuals with the variant: 2 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 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Fundacion Hipercolesterolemia Familiar Study: SAFEHEART Accession: SCV000607460.1 First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016
Pathogenic (Mar 21, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017117.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jul 08, 2021)	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: SCV001225261.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 20809525‚ 28645073‚ 10206683‚ 27824480‚ 20145306 Comment: This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in LDLR … (more) This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 10206683, 27824480, 20145306). This variant is also described as Q133X in the literature. ClinVar contains an entry for this variant (Variation ID: 251237). This sequence change creates a premature translational stop signal (p.Gln154*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. (less)
Pathogenic (Apr 05, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003959478.2 First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024	Publications: PubMed (17) PubMed: 10206683‚ 11668640‚ 15241806‚ 16542394‚ 16627557‚ 17539906‚ 18096825‚ 20145306‚ 22244043‚ 27765764‚ 27784735‚ 30312929‚ 33303402‚ 33740630‚ 33955087‚ 34037665‚ 34456049 Comment: The c.460C>T (p.Q154) alteration, located in exon 4 (coding exon 4) of the LDLR gene, consists of a C to T substitution at nucleotide position … (more) The c.460C>T (p.Q154) alteration, located in exon 4 (coding exon 4) of the LDLR gene, consists of a C to T substitution at nucleotide position 460. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 154. 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, which is also known as p.Q133*, has been reported in numerous individuals with familial hypercholesterolemia (FH) (Cenarro, 1998; García-García, 2001; Mozas, 2004; Blesa, 2006; Brusgaard, 2006; Taylor, 2007; Junyent, 2008; Chmara, 2010; Wang, 2016; Ibarretxe, 2018; Benedek, 2021; Leren, 2021; Gill, 2021; Marco-Benedí, 2022) Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Jul 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198647.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Jan 01, 2023)	no assertion criteria provided Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: germline	Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham Accession: SCV005205808.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Publications: PubMed (2) PubMed: 20809525‚ 28645073 Comment: This alteration changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 154 and is expected to result in … (more) This alteration changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 154 and is expected to result in loss of function by premature protein truncation .This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (less) Age: 35-65 years Ethnicity/Population group: Asian- South Indian

Comment:

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 10206683, 27824480, 20145306). This variant is also described as Q133X in the literature. ClinVar contains an entry for this variant (Variation ID: 251237). This sequence change creates a premature translational stop signal (p.Gln154*) in the LDLR gene. It is expected to result in an absent or disrupted protein product.

Comment:

The c.460C>T (p.Q154*) alteration, located in exon 4 (coding exon 4) of the LDLR gene, consists of a C to T substitution at nucleotide position 460. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 154. 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, which is also known as p.Q133*, has been reported in numerous individuals with familial hypercholesterolemia (FH) (Cenarro, 1998; García-García, 2001; Mozas, 2004; Blesa, 2006; Brusgaard, 2006; Taylor, 2007; Junyent, 2008; Chmara, 2010; Wang, 2016; Ibarretxe, 2018; Benedek, 2021; Leren, 2021; Gill, 2021; Marco-Benedí, 2022) Based on the available evidence, this alteration is classified as pathogenic.

Comment:

This alteration changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 154 and is expected to result in loss of function by premature protein truncation .This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD)

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
Lipoprotein(a) in hereditary hypercholesterolemia: Influence of the genetic cause, defective gene and type of mutation.	Marco-Benedí V	Atherosclerosis	2022	PMID: 34456049
Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis.	Sturm AC	JAMA cardiology	2021	PMID: 34037665
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
Molecular genetic testing for autosomal dominant hypercholesterolemia in 29,449 Norwegian index patients and 14,230 relatives during the years 1993-2020.	Leren TP	Atherosclerosis	2021	PMID: 33740630
Combined hyperlipidemia is genetically similar to isolated hypertriglyceridemia.	Gill PK	Journal of clinical lipidology	2021	PMID: 33303402
Detecting familial hypercholesterolemia earlier in life by actively searching for affected children:The DECOPIN project.	Ibarretxe D	Atherosclerosis	2018	PMID: 30312929
Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene.	Jiang L	Atherosclerosis	2017	PMID: 28645073
The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey.	Gabčová D	Physiological research	2017	PMID: 27824480
Homozygous Familial Hypercholesterolemia in Spain: Prevalence and Phenotype-Genotype Relationship.	Sánchez-Hernández RM	Circulation. Cardiovascular genetics	2016	PMID: 27784735
Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically.	Wang J	Arteriosclerosis, thrombosis, and vascular biology	2016	PMID: 27765764
Molecular characterization of familial hypercholesterolemia in Spain.	Palacios L	Atherosclerosis	2012	PMID: 22244043
Molecular spectrum of autosomal dominant hypercholesterolemia in France.	Marduel M	Human mutation	2010	PMID: 20809525
Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations.	Chmara M	Journal of applied genetics	2010	PMID: 20145306
Femoral atherosclerosis in heterozygous familial hypercholesterolemia: influence of the genetic defect.	Junyent M	Arteriosclerosis, thrombosis, and vascular biology	2008	PMID: 18096825
Multiplex ARMS analysis to detect 13 common mutations in familial hypercholesterolaemia.	Taylor A	Clinical genetics	2007	PMID: 17539906
Analysis of sequence variations in the LDL receptor gene in Spain: general gene screening or search for specific alterations?	Blesa S	Clinical chemistry	2006	PMID: 16627557
Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia.	Brusgaard K	Clinical genetics	2006	PMID: 16542394
Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR.	Mozas P	Human mutation	2004	PMID: 15241806
Molecular genetics of familial hypercholesterolemia in Spain: Ten novel LDLR mutations and population analysis.	García-García AB	Human mutation	2001	PMID: 11668640
Identification of recurrent and novel mutations in the LDL receptor gene in Spanish patients with familial hypercholesterolemia. Mutations in brief no. 135. Online.	Cenarro A	Human mutation	1998	PMID: 10206683
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Text-mined citations for rs879254534 ...

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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000527.5(LDLR):c.460C>T (p.Gln154Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs879254534 ...