VCV000375810.9 - ClinVar

NM_000527.5(LDLR):c.1187del

Germline

Classification

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

Pathogenic
Pathogenic (5)

5 out of 6 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.1187del

Variation ID: 375810 Accession: VCV000375810.9

Type and length

Deletion, 1 bp

Location

Cytogenetic: 19p13.2 19: 11113277 (GRCh38) [ NCBI UCSC ] 19: 11223953 (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	Mar 8, 2017	Feb 23, 2026	Oct 21, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.1187del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_000527.4:c.1187delG
NC_000019.10:g.11113278del
NC_000019.9:g.11223954del
NG_009060.1:g.28898del
LRG_274:g.28898del
LRG_274t1:c.1187del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000019.10:11113276:GG:G

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: CA16602325 dbSNP: rs1057519667 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	4568	4909

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	Sep 1, 2022	RCV000417253.9
not provided	Pathogenic (1)	criteria provided, single submitter	Oct 21, 2024	RCV004999375.1
Familial hypercholesterolemia	Pathogenic (1)	criteria provided, single submitter	Jun 17, 2023	RCV003581655.4

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.	Expand all rows Collapse all rows 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 (Dec 16, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypercholesterolemia, familial, 1	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix Accession: SCV000503312.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: show subject mutated among 2600 FH index cases screened = 1 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

pathogenic (Oct 21, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria)	not provided	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV005625805.1 First in ClinVar: Jan 19, 2025 Last updated: Jan 19, 2025	Publications: PubMed (2) PubMed: 30710474‚ 34297352 Comment: show The LDLR c.1187del (p.Gly396Alafs*17) variant alters the translational reading frame of the LDLR mRNA and causes the premature termination of LDLR protein synthesis. In the published literature, this variant has been reported in individual(s) with a personal and/or family history of familial hypercholesterolemia (PMIDs: 34297352 (2021), 30710474 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (May 24, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypercholesterolemia, familial, 1	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II Accession: SCV001653625.1 First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021	Publications: PubMed (1) PubMed: 30710474 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Ethnicity/Population group: Caucasian Geographic origin: Italy

Pathogenic (Sep 01, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypercholesterolemia, familial, 1	3billion Accession: SCV002572880.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Comment: show The variant is not observed in the gnomAD v2.1.1 dataset. The variant in the canonical splice site is predicted to alter splicing, resulting in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000375810). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Clinical Features: Xanthomatosis (present) Zygosity: 1 Single Heterozygote Platform type: whole exome sequencing Platform name: NovaSeq

Pathogenic (Jun 17, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Familial hypercholesterolemia	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004272270.3 First in ClinVar: Feb 14, 2024 Last updated: Feb 23, 2026	Publications: PubMed (3) PubMed: 20809525‚ 28645073‚ 30710474 Comment: show This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly396Alafs*17) 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 premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 30710474). ClinVar contains an entry for this variant (Variation ID: 375810). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	Familial hypercholesterolemia	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum Accession: SCV000606349.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017	Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

Comment:

The LDLR c.1187del (p.Gly396Alafs*17) variant alters the translational reading frame of the LDLR mRNA and causes the premature termination of LDLR protein synthesis. In the published literature, this variant has been reported in individual(s) with a personal and/or family history of familial hypercholesterolemia (PMIDs: 34297352 (2021), 30710474 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. The variant in the canonical splice site is predicted to alter splicing, resulting in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000375810). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly396Alafs*17) 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 premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 30710474). ClinVar contains an entry for this variant (Variation ID: 375810). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic spectrum of familial hypercholesterolemia and correlations with clinical expression: Implications for diagnosis improvement.	Di Taranto MD	Clinical genetics	2021	PMID: 34297352
Lipid profile and genetic status in a familial hypercholesterolemia pediatric population: exploring the LDL/HDL ratio.	Di Taranto MD	Clinical chemistry and laboratory medicine	2019	PMID: 30710474
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

Text-mined citations for rs1057519667 ...

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 Apr 13, 2026