VCV000003711.1 - ClinVar

NM_000527.5(LDLR):c.2311+251_*813del

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.

(1)

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

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000527.5(LDLR):c.2311+251_*813del

Variation ID: 3711 Accession: VCV000003711.1

Type and length

Deletion, 8,535 bp

Location

Cytogenetic: 19p13.2 19: 11123590-11132124 (GRCh38) [ NCBI UCSC ] 19: 11234266-11242800 (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	Apr 4, 2013	Apr 4, 2013	Dec 1, 1992

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.2311+251_*813del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor splice donor
NM_001195798.2:c.2311+251_*813del		splice acceptor splice donor
NM_001195799.2:c.2188+251_*813del		splice acceptor splice donor
NM_001195800.2:c.1807+251_*813del		splice acceptor splice donor
NM_001195803.2:c.1777+251_*813del		splice acceptor splice donor
NC_000019.10:g.11123595_11132129del
NC_000019.9:g.11234271_11242805del
NG_009060.1:g.39215_47749del
LRG_274:g.39215_47749del

... more HGVS ... less HGVS

Protein change

Other names

FH Helsinki
FH Osaka 1
FH Rochester
EX16-18DEL

Canonical SPDI

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: CA250473 dbVar: nssv3761563 dbVar: nsv1067857 OMIM: 606945.0029 VarSome

Comment on variant

Deletion resulting in loss of exons 16-18 from gene LDLR translation.

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 (1)	no assertion criteria provided	Dec 1, 1992	RCV000003905.5

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 (Dec 01, 1992)	no assertion criteria provided Method: literature only	FH ROCHESTER Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024069.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (5) PubMed: 3924410‚ 3815525‚ 2760198‚ 1362925‚ 1372927 Comment on evidence: In an American patient with FH (143890), Lehrman et al. (1985) found deletion of exons 16, 17, and part of 18, due apparently to Alu-Alu … (more) In an American patient with FH (143890), Lehrman et al. (1985) found deletion of exons 16, 17, and part of 18, due apparently to Alu-Alu recombination. The same mutation was found in Japanese by Lehrman et al. (1987) and in many Finns by Aalto-Setala et al. (1989). A 9.5-kb deletion extended from intron 15 to exon 18. Because of loss of the domains encoded by exons 16, 17, and 18, the carboxy-terminal portion of the normal receptor, comprising amino acids 750-839, has been replaced by an unrelated stretch of 55 amino acids. This particular mutation was found in 23 of 46 unrelated Finnish FH patients with an established functional defect of LDLR. In cultured fibroblasts, both receptor-mediated binding and internalization of LDL were reduced on the average by 25 and 50%, respectively. Aalto-Setala et al. (1989) referred to the mutation as FH-Helsinki. Rodningen et al. (1992) found the same mutation in 3 out of 181 (1.7%) unrelated Norwegian FH subjects. All 3 showed the same haplotype. Aalto-Setala et al. (1992) found that the FH-Helsinki mutation was present in 75 (38%) of 199 unrelated Finnish patients with hypercholesterolemia. The prevalence ranged from 26 to 58% in different areas of Finland, with the striking exception of the North Karelia region where only 1 of 26 (4%) FH patients carried the FH-Helsinki allele. (less)

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Prevalence and geographical distribution of major LDL receptor gene rearrangements in Finland.	Aalto-Setälä K	Journal of internal medicine	1992	PMID: 1372927
A 9.6 kilobase deletion in the low density lipoprotein receptor gene in Norwegian familial hypercholesterolemia subjects.	Rødningen OK	Clinical genetics	1992	PMID: 1362925
Finnish type of low density lipoprotein receptor gene mutation (FH-Helsinki) deletes exons encoding the carboxy-terminal part of the receptor and creates an internalization-defective phenotype.	Aalto-Setälä K	The Journal of clinical investigation	1989	PMID: 2760198
Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia.	Lehrman MA	Cell	1987	PMID: 3815525
Internalization-defective LDL receptors produced by genes with nonsense and frameshift mutations that truncate the cytoplasmic domain.	Lehrman MA	Cell	1985	PMID: 3924410

Text-mined citations for this variant ...

Record last updated Aug 06, 2023

ClinVar Genomic variation as it relates to human health

NM_000527.5(LDLR):c.2311+251_*813del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...