VCV000252087.4 - ClinVar

NM_000527.5(LDLR):c.1859G>A (p.Trp620Ter)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic

4 out of 4 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000527.5(LDLR):c.1859G>A (p.Trp620Ter)

Variation ID: 252087 Accession: VCV000252087.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11120105 (GRCh38) [ NCBI UCSC ] 19: 11230781 (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	Mar 4, 2025	Sep 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.1859G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Trp620Ter	nonsense
NM_001195798.2:c.1859G>A	NP_001182727.1:p.Trp620Ter	nonsense
NM_001195799.2:c.1736G>A	NP_001182728.1:p.Trp579Ter	nonsense
NM_001195800.2:c.1355G>A	NP_001182729.1:p.Trp452Ter	nonsense
NM_001195803.2:c.1478G>A	NP_001182732.1:p.Trp493Ter	nonsense
NC_000019.10:g.11120105G>A
NC_000019.9:g.11230781G>A
NG_009060.1:g.35725G>A
LRG_274:g.35725G>A
LRG_274t1:c.1859G>A	LRG_274p1:p.Trp620Ter

... more HGVS ... less HGVS

Protein change

W620*, W493*, W579*, W452*

Other names

Canonical SPDI

NC_000019.10:11120104:G:A

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: CA10585658 LDLR-LOVD, British Heart Foundation: LDLR_001208 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	4220	4521

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 (3)	criteria provided, multiple submitters, no conflicts	Mar 30, 2017	RCV000237737.5
Familial hypercholesterolemia	Pathogenic (1)	criteria provided, single submitter	Sep 30, 2024	RCV003581634.3

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 30, 2017) C Contributing to aggregate classification	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: SCV000583898.1 First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 Comment: ACMG Guidelines: Pathogenic (i)	Number of individuals with the variant: 1 Clinical Features: Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present) Comment on clinical features: "Dutch Lipid Clinic" Diagnostic Scoring ESC/EAS Guidelines 2016 - PMID: 27567407 Indication for testing: Familial Hypercholesterolemia Geographic origin: France Comment on evidence: Dutch Lipid Clinic Scoring : Probable FH Secondary finding: no
Pathogenic (Mar 01, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory of Genetics and Molecular Cardiology, University of São Paulo Study: HipercolBrasil Accession: SCV000588618.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017
Pathogenic (Sep 30, 2024) C Contributing to aggregate classification	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: SCV004298374.2 First in ClinVar: Feb 14, 2024 Last updated: Mar 04, 2025	Publications: PubMed (3) PubMed: 20809525‚ 28645073‚ 11737238 Comment: This sequence change creates a premature translational stop signal (p.Trp620) 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.Trp620) 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 individual(s) with familial hypercholesterolemia (PMID: 11737238). This variant is also known as W599X. ClinVar contains an entry for this variant (Variation ID: 252087). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 25, 2016) C Contributing to aggregate classification	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: SCV000295719.2 First in ClinVar: Jul 29, 2016 Last updated: Aug 13, 2017	Publications: PubMed (2) PubMed: 11737238‚ 23375686 Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1

Comment:

This sequence change creates a premature translational stop signal (p.Trp620*) 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 individual(s) with familial hypercholesterolemia (PMID: 11737238). This variant is also known as W599X. ClinVar contains an entry for this variant (Variation ID: 252087). For these reasons, this variant has been classified as Pathogenic.

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
Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene.	Jiang L	Atherosclerosis	2017	PMID: 28645073
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.	Bertolini S	Atherosclerosis	2013	PMID: 23375686
Molecular spectrum of autosomal dominant hypercholesterolemia in France.	Marduel M	Human mutation	2010	PMID: 20809525
Impact of genetic defects on atherosclerosis in patients suspected of familial hypercholesterolaemia.	Descamps OS	European journal of clinical investigation	2001	PMID: 11737238

Text-mined citations for this variant ...

Record last updated Mar 11, 2025

ClinVar Genomic variation as it relates to human health

NM_000527.5(LDLR):c.1859G>A (p.Trp620Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...