NC_000019.10:g.11089393C>T AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Mar 20, 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:: RCV000237296.12

Allele description [Variation Report for NC_000019.10:g.11089393C>T]

NC_000019.10:g.11089393C>T

Genes:

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

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NC_000019.10:g.11089393C>T

HGVS:

NC_000019.10:g.11089393C>T
NG_009060.1:g.5013C>T
NM_000527.4:c.-156C>T
NM_001195798.1:c.-156C>T
NM_001195799.1:c.-156C>T
NM_001195800.1:c.-156C>T
NM_001195803.1:c.-156C>T
LRG_274t1:c.-156C>T
LRG_274:g.5013C>T
NC_000019.9:g.11200069C>T
NR_163945.1:n.267G>A
c.-156C>T

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001112; dbSNP: rs879254364

NCBI 1000 Genomes Browser:

rs879254364

Molecular consequence:

NR_163945.1:n.267G>A - 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

Recent activity

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Escherichia coli isolate KR2730 genome assembly, contig: NODE_1_length_379340_co...
Escherichia coli isolate KR2730 genome assembly, contig: NODE_1_length_379340_cov_13450850, whole genome shotgun sequence
gi|1927540634|emb|CACSHK010000111.1

Nucleotide
ifi44d interferon-induced protein 44d [Danio rerio]
ifi44d interferon-induced protein 44d [Danio rerio]
Gene ID:795887

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000294377	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004022391	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain significance (Mar 20, 2023)	germline	curation	Citation Link,
SCV004840242	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 20, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 14974088, 21382890, 28104544, 31395865, 31947532, 32977124, 33740630, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000294377

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Likely pathogenic
(Mar 25, 2016)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV004022391

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)

Uncertain significance
(Mar 20, 2023)

germline

curation

Citation Link,

SCV004840242

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 20, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Molecular characterization of familial hypercholesterolemia in German and Greek patients.

Dedoussis GV, Genschel J, Bochow B, Pitsavos C, Skoumas J, Prassa M, Lkhagvasuren S, Toutouzas P, Vogt A, Kassner U, Thomas HP, Schmidt H.

Hum Mutat. 2004 Mar;23(3):285-6.

PubMed [citation]

PMID:: 14974088

Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children.

van der Graaf A, Avis HJ, Kusters DM, Vissers MN, Hutten BA, Defesche JC, Huijgen R, Fouchier SW, Wijburg FA, Kastelein JJ, Wiegman A.

Circulation. 2011 Mar 22;123(11):1167-73. doi: 10.1161/CIRCULATIONAHA.110.979450. Epub 2011 Mar 7.

PubMed [citation]

PMID:: 21382890

See all PubMed Citations (8)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294377.2

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

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

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV004022391.1

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

Description

The NM_000527.4(LDLR):c.-156C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_supporting, PS4_supporting, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PS3_supporting - Level 3 assay: PMID 31395865: Heterologous cells, luciferase assays - result - luciferase activity 15-17% of wild-type (repressing variant). ---- functional study is consistent with damaging effect. PS4_supporting - Variant meets PM2 and is identified in 2 index cases with definite FH: 1 index case with CT=439, LDL=377, severe CAD and Achilles tendon xanthomata from Germany (PMID: 14974088), and 1 index case with LDL >13 mmol/L, pCHD and tendon xanthomas from Italy (PMID: 31947532). PP4 - Variant meets PM2 and is identified in 2 index cases with definite FH (see PS4 for details), after alternative causes for high cholesterol were excluded.

#	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, SCV004840242.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (8)

Description

This variant is located in the SREBP binding site in the promoter region of the LDLR gene. An experimental functional study measuring luciferase activity in transfected HepG2 cells has shown that this variant causes a significant decrease in LDLR gene expression (PMID: 31395865). This variant has been reported in four heterozygous individuals affected with familial hypercholesterolemia (PMID: 14974088, 21382890, 28104544, 33740630). This variant has also been observed in homozygous state in one individual affected with severe homozygous familial hypercholesterolemia (PMID: 31947532, 32977124). It has been shown that this variant segregates with disease in two affected individuals in one family (PMID: 14974088). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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

Last Updated: Oct 26, 2024

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