VCV000252104.9 - ClinVar

NM_000527.5(LDLR):c.1886del (p.Phe629fs)

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.

(6)

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

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.1886del (p.Phe629fs)

Variation ID: 252104 Accession: VCV000252104.9

Type and length

Deletion, 1 bp

Location

Cytogenetic: 19p13.2 19: 11120129 (GRCh38) [ NCBI UCSC ] 19: 11230805 (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	Oct 15, 2016	May 1, 2024	Dec 22, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.1886del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Phe629fs	frameshift
NM_000527.4:c.1886delT
NM_001195798.2:c.1886del	NP_001182727.1:p.Phe629fs	frameshift
NM_001195799.2:c.1763del	NP_001182728.1:p.Phe588fs	frameshift
NM_001195800.2:c.1382del	NP_001182729.1:p.Phe461fs	frameshift
NM_001195803.2:c.1505del	NP_001182732.1:p.Phe502fs	frameshift
NC_000019.10:g.11120132del
NC_000019.9:g.11230808del
NG_009060.1:g.35752del
LRG_274:g.35752del

... more HGVS ... less HGVS

Protein change

F502fs, F588fs, F629fs, F461fs

Other names

Canonical SPDI

NC_000019.10:11120128:TTTT:TTT

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: CA10585675 LDLR-LOVD, British Heart Foundation: LDLR_000261 dbSNP: rs879255068 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 (4)	criteria provided, multiple submitters, no conflicts	Dec 16, 2016	RCV000237279.6
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Jun 30, 2020	RCV002411104.2
Familial hypercholesterolemia	Pathogenic (1)	criteria provided, single submitter	Dec 22, 2020	RCV002229815.6

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: SCV000295741.2 First in ClinVar: Jul 29, 2016 Last updated: Oct 10, 2018	Publications: PubMed (2) PubMed: 17765246‚ 20809525 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: research	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge Accession: SCV000322985.1 First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016	Comment: 0/200 non-FH alleles Observation 1: Observation 2:
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: SCV000503431.1 First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016	Comment: subject mutated among 2600 FH index cases screened = 1 Number of individuals with the variant: 1
Pathogenic (Dec 22, 2020)	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: SCV000824578.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 28492532‚ 17765246‚ 20809525‚ 28645073 Comment: This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 17765246, 20809525). This variant is also known as F608fsX642 in the literature. … (more) This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 17765246, 20809525). This variant is also known as F608fsX642 in the literature. ClinVar contains an entry for this variant (Variation ID: 252104). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Phe629Serfs*36) 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). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jun 30, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002717766.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 17765246‚ 20809525‚ 28964736 Comment: The c.1886delT pathogenic mutation, located in coding exon 13 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 1886, causing … (more) The c.1886delT pathogenic mutation, located in coding exon 13 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 1886, causing a translational frameshift with a predicted alternate stop codon (p.F629Sfs*36). This alteration has been reported in multiple individuals from familial hypercholesterolemia cohorts and has been alternatively reported as F608fsX642 (Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Defesche JC et al. J Clin Lipidol Sep;11:1338-1346.e7).. 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 (-)	no assertion criteria provided Method: research	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum Accession: SCV000606550.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017

Comment:

This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 17765246, 20809525). This variant is also known as F608fsX642 in the literature. ClinVar contains an entry for this variant (Variation ID: 252104). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Phe629Serfs*36) 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). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.1886delT pathogenic mutation, located in coding exon 13 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 1886, causing a translational frameshift with a predicted alternate stop codon (p.F629Sfs*36). This alteration has been reported in multiple individuals from familial hypercholesterolemia cohorts and has been alternatively reported as F608fsX642 (Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Defesche JC et al. J Clin Lipidol Sep;11:1338-1346.e7).. 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
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
Molecular spectrum of autosomal dominant hypercholesterolemia in France.	Marduel M	Human mutation	2010	PMID: 20809525
Familial hypercholesterolaemia in Portugal.	Bourbon M	Atherosclerosis	2008	PMID: 17765246

Text-mined citations for rs879255068 ...

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.1886del (p.Phe629fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs879255068 ...