VCV000252214.5 - ClinVar

NM_000527.5(LDLR):c.2092del (p.Cys698fs)

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.

(5)

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.2092del (p.Cys698fs)

Variation ID: 252214 Accession: VCV000252214.5

Type and length

Deletion, 1 bp

Location

Cytogenetic: 19p13.2 19: 11120474 (GRCh38) [ NCBI UCSC ] 19: 11231150 (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	Sep 9, 2017	Feb 14, 2024	Feb 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.2092del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Cys698fs	frameshift
NM_000527.4:c.2092delT
NM_001195798.2:c.2092del	NP_001182727.1:p.Cys698fs	frameshift
NM_001195799.2:c.1969del	NP_001182728.1:p.Cys657fs	frameshift
NM_001195800.2:c.1588del	NP_001182729.1:p.Cys530fs	frameshift
NM_001195803.2:c.1606+241del		intron variant
NC_000019.10:g.11120474del
NC_000019.9:g.11231150del
NG_009060.1:g.36094del
LRG_274:g.36094del
LRG_274t1:c.2092del	LRG_274p1:p.Cys698fs

... more HGVS ... less HGVS

Protein change

C657fs, C530fs, C698fs

Other names

FH New York-4

Canonical SPDI

NC_000019.10:11120473: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: CA10585768 LDLR-LOVD, British Heart Foundation: LDLR_001598 dbSNP: rs879255135 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 (4)	criteria provided, multiple submitters, no conflicts	Nov 3, 2022	RCV000238404.6
Familial hypercholesterolemia	Pathogenic (1)	criteria provided, single submitter	Feb 20, 2023	RCV003581640.2

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: SCV000295866.2 First in ClinVar: Jul 29, 2016 Last updated: Sep 09, 2017	Publications: PubMed (2) PubMed: 1301956‚ 9664576 Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1
Pathogenic (Mar 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation, literature only	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: unknown, not applicable Allele origin: germline, not applicable	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge Accession: SCV000599403.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (1) PubMed: 1301956 Observation 1: Observation 2: Comment on evidence: Assay Description:Htz patients' fibroblasts, 125I-LDL assays Result: 35-45% LDLR activity
Pathogenic (Jun 04, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: germline	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia Accession: SCV001432558.1 First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020	Number of individuals with the variant: 1 Clinical Features: Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Likely pathogenic (Nov 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003831288.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Feb 20, 2023)	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: SCV004297877.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 20809525‚ 28645073‚ 11845603 Comment: This sequence change creates a premature translational stop signal (p.Cys698Alafs11) 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.Cys698Alafs11) 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 hypercholesterolemia (PMID: 11845603). ClinVar contains an entry for this variant (Variation ID: 252214). For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

This sequence change creates a premature translational stop signal (p.Cys698Alafs*11) 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 hypercholesterolemia (PMID: 11845603). ClinVar contains an entry for this variant (Variation ID: 252214). 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
Molecular spectrum of autosomal dominant hypercholesterolemia in France.	Marduel M	Human mutation	2010	PMID: 20809525
Clinical versus molecular diagnosis of heterozygous familial hypercholesterolaemia in the diverse South African population.	Vergotine J	South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde	2001	PMID: 11845603
Mutation analysis in familial hypercholesterolemia patients of different ancestries: identification of three novel LDLR gene mutations.	Callis M	Molecular and cellular probes	1998	PMID: 9664576
Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.	Hobbs HH	Human mutation	1992	PMID: 1301956

Text-mined citations for rs879255135 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000527.5(LDLR):c.2092del (p.Cys698fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs879255135 ...