NG_009060.1(LDLR):g.4976CTC[2] AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Apr 28, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000505217.14

Allele description [Variation Report for NG_009060.1(LDLR):g.4976CTC[2]]

NG_009060.1(LDLR):g.4976CTC[2]

Genes:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
LDLR-AS1:LDLR antisense RNA 1 [Gene - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NG_009060.1(LDLR):g.4976CTC[2]

Other names:

NM_000527.4(LDLR):c.-187_-185del

HGVS:

NC_000019.10:g.11089356CTC[2]
NC_000019.9:g.11200038_11200040del
NG_009060.1:g.4976CTC[2]
NG_009060.1:g.4982_4984del
LRG_274t1:c.-187_-185del
LRG_274:g.4976CTC[2]
LRG_274:g.4982_4984del
NC_000019.10:g.11089356CTC[2]
NC_000019.9:g.11200032CTC[2]
NC_000019.9:g.11200032_11200034del
NC_000019.9:g.11200038_11200040del
NG_009060.1:g.4982_4984del
NM_000527.4:c.-187_-185del
NR_163945.1:n.296GAG[2]

Links:

dbSNP: rs1270618112

NCBI 1000 Genomes Browser:

rs1270618112

Molecular consequence:

NR_163945.1:n.296GAG[2] - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000599296	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline, not applicable	curation, literature only	PubMed (2) [See all records that cite these PMIDs] 25741868, 9610768
SCV000605982	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV004834517	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005375290	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain Significance (Apr 28, 2023)	germline	curation	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing, research, curation

Citations

PubMed

A 3-basepair deletion in repeat 1 of the LDL receptor promoter reduces transcriptional activity in a South African Pedi.

Peeters AV, Kotze MJ, Scholtz CL, De Waal LF, Rubinsztein DC, Coetzee GA, Zuliani G, Streiff R, Liu J, van der Westhuyzen DR.

J Lipid Res. 1998 May;39(5):1021-4.

PubMed [citation]

PMID:: 9610768

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000599296.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)
2	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

"Assay Description:Heterologous cells (HepG2), luciferase assays"

PubMed [ID: 9610768]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided
2	not applicable	not applicable	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000605982.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004834517.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV005375290.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_000527.5 (LDLR):c.-187_185del variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 April 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD version 2.1.1). PS3_Supporting: Level 3 experiment, heterologous cells (HepG2) were used for luciferase assays, 8% reporter gene expression observed, PMID 9610768 (Peeters et al., 1998).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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