VCV003076048.1 - ClinVar

NC_000019.10:g.(?_11110652)_(11111639_?)del

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

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_000019.10:g.(?_11110652)_(11111639_?)del

Variation ID: 3076048 Accession: VCV003076048.1

Type and length

Deletion, 988 bp

Location

Cytogenetic: 19p13.2 19: 11110652-11111639 (GRCh38) [ 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 20, 2024	Apr 20, 2024	Nov 3, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NC_000019.10:g.(?_11110652)_(11111639_?)del

Protein change

Other names

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

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.
Homozygous familial hypercholesterolemia	Pathogenic (1)	criteria provided, single submitter	Nov 3, 2017	RCV004018366.1

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 (Nov 03, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Homozygous familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848129.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (6) PubMed: 1301956‚ 9048913‚ 20145306‚ 3198114‚ 9254862‚ 22698793 Comment: The c.941-?_1186+?del variant in LDLR (legacy names: FH Cape Town-2, FH Leuven, and FH Leiden-1) has been reported in >5 individuals with heterozygous familial hypercholesterolemia … (more) The c.941-?_1186+?del variant in LDLR (legacy names: FH Cape Town-2, FH Leuven, and FH Leiden-1) has been reported in >5 individuals with heterozygous familial hypercholesterolemia (FH) and at least 2 individuals with homozygous FH as well as segregated with disease in at least 10 affected relatives from multiple families (Henderson 1988, Peeters 1997, Chae 1997, Chmara 2010, Tichy 2012). It was also absent from large population studies. This variant is reported in ClinVar (Variation IDs: 3701, 441201). This variant is an in-frame deletion of exons 7 and 8, which may result in no protein being produced or a protein product lacking exons 7 and 8. In vitro functional studies provide some evidence that there is residual protein with only 2-5% receptor activity in homozygous cell lines (Hobbs 1992). In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon segregation studies, absence from controls, and functional evidence. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS3_Moderate, PS4_Moderate. (less)

Comment:

The c.941-?_1186+?del variant in LDLR (legacy names: FH Cape Town-2, FH Leuven, and FH Leiden-1) has been reported in >5 individuals with heterozygous familial hypercholesterolemia (FH) and at least 2 individuals with homozygous FH as well as segregated with disease in at least 10 affected relatives from multiple families (Henderson 1988, Peeters 1997, Chae 1997, Chmara 2010, Tichy 2012). It was also absent from large population studies. This variant is reported in ClinVar (Variation IDs: 3701, 441201). This variant is an in-frame deletion of exons 7 and 8, which may result in no protein being produced or a protein product lacking exons 7 and 8. In vitro functional studies provide some evidence that there is residual protein with only 2-5% receptor activity in homozygous cell lines (Hobbs 1992). In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon segregation studies, absence from controls, and functional evidence. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS3_Moderate, PS4_Moderate.

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
The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations.	Tichý L	Atherosclerosis	2012	PMID: 22698793
Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations.	Chmara M	Journal of applied genetics	2010	PMID: 20145306
Mutational and genetic origin of LDL receptor gene mutations detected in both Belgian and Dutch familial hypercholesterolemics.	Peeters AV	Human genetics	1997	PMID: 9254862
Two partial deletion mutations involving the same Alu sequence within intron 8 of the LDL receptor gene in Korean patients with familial hypercholesterolemia.	Chae JJ	Human genetics	1997	PMID: 9048913
Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.	Hobbs HH	Human mutation	1992	PMID: 1301956
A new LDL receptor gene deletion mutation in the South African population.	Henderson HE	Human genetics	1988	PMID: 3198114

Text-mined citations for this variant ...

Record last updated May 08, 2024

ClinVar Genomic variation as it relates to human health

NC_000019.10:g.(?_11110652)_(11111639_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...