VCV000237865.8 - ClinVar

NM_000527.5(LDLR):c.1706-2A>T

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/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.1706-2A>T

Variation ID: 237865 Accession: VCV000237865.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11116857 (GRCh38) [ NCBI UCSC ] 19: 11227533 (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	Jul 29, 2016	Apr 6, 2024	Mar 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.1706-2A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001195798.2:c.1706-2A>T		splice acceptor
NM_001195799.2:c.1583-2A>T		splice acceptor
NM_001195800.2:c.1202-2A>T		splice acceptor
NM_001195803.2:c.1325-2A>T		splice acceptor
NC_000019.10:g.11116857A>T
NC_000019.9:g.11227533A>T
NG_009060.1:g.32477A>T
LRG_274:g.32477A>T
LRG_274t1:c.1706-2A>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000019.10:11116856:A: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: CA10583778 LDLR-LOVD, British Heart Foundation: LDLR_001500 dbSNP: rs878854027 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	4075	4351

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 (5)	criteria provided, multiple submitters, no conflicts	Mar 29, 2024	RCV000231584.8
Familial hypercholesterolemia	Pathogenic (1)	criteria provided, single submitter	Apr 4, 2021	RCV002229340.6

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: SCV000295601.2 First in ClinVar: Jul 29, 2016 Last updated: Sep 30, 2017	Publications: PubMed (2) PubMed: 20809525‚ 22129472 Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1
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: SCV000503395.1 First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016	Comment: subject mutated among 2600 FH index cases screened = 1 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: SCV000599383.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (1) PubMed: 22129472 Observation 1: Observation 2: Comment on evidence: Assay Description:Hmz; Htz patients' lymphocytes, RNA assays Result: 5-12%; 23-14% expression, skipping of the first 10 nucleotides from exon 12 (p.Asp569Valfs*93)
Pathogenic (Apr 04, 2021)	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: SCV000285017.6 First in ClinVar: Jul 03, 2016 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 22129472 Comment: For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with a 10 nucleotide deletion in exon … (more) For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with a 10 nucleotide deletion in exon 12, which introduces a premature termination codon (PMID: 22129472). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 22129472). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 237865). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 11 of the LDLR gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. (less)
Likely pathogenic (Mar 29, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004807848.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
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: SCV000606495.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017

Comment:

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with a 10 nucleotide deletion in exon 12, which introduces a premature termination codon (PMID: 22129472). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 22129472). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 237865). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 11 of the LDLR gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.

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 Arabic allele: a single base pair substitution activates a 10-base downstream cryptic splice acceptor site in exon 12 of LDLR and severely decreases LDLR expression in two unrelated Arab families with familial hypercholesterolemia.	Shawar SM	Atherosclerosis	2012	PMID: 22129472
Molecular spectrum of autosomal dominant hypercholesterolemia in France.	Marduel M	Human mutation	2010	PMID: 20809525

Text-mined citations for rs878854027 ...

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.1706-2A>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs878854027 ...