NC_000019.10:g.11089396C>T AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 15, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000775251.18

Allele description [Variation Report for NC_000019.10:g.11089396C>T]

NC_000019.10:g.11089396C>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.11089396C>T

HGVS:

NC_000019.10:g.11089396C>T
NG_009060.1:g.5016C>T
NM_000527.4:c.-153C>T
NM_001195798.1:c.-153C>T
NM_001195799.1:c.-153C>T
NM_001195800.1:c.-153C>T
NM_001195803.1:c.-153C>T
LRG_274t1:c.-153C>T
LRG_274:g.5016C>T
NC_000019.9:g.11200072C>T
NR_163945.1:n.264G>A
c.-153C>T

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001116; dbSNP: rs879254366

NCBI 1000 Genomes Browser:

rs879254366

Molecular consequence:

NR_163945.1:n.264G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

Recent activity

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JGI_CAAP6293.rev NIH_XGC_tropInt1 Xenopus tropicalis cDNA clone IMAGE:7712751 3'...
JGI_CAAP6293.rev NIH_XGC_tropInt1 Xenopus tropicalis cDNA clone IMAGE:7712751 3', mRNA sequence
gi|58783810|gnl|dbEST|27677202|gb|C 83.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000909510	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 15, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15303010, 31395865, 35052492, 25741868
SCV002312518	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 12, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15303010, 31395865, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000909510

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 15, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002312518

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 12, 2021)

germline

clinical testing

PubMed (3)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Establishing the Mutational Spectrum of Hungarian Patients with Familial Hypercholesterolemia.

Madar L, Juhász L, Szűcs Z, Kerkovits L, Harangi M, Balogh I.

Genes (Basel). 2022 Jan 15;13(1). doi:pii: 153. 10.3390/genes13010153.

PubMed [citation]

PMID:: 35052492
PMCID:: PMC8775528

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

See all PubMed Citations (5)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000909510.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant is located in the conserved sterol-dependent regulatory element 2 (SRE2) in the promoter region of the LDLR gene. This variant is also known as -60C>T based on the position calculated from the transcription start site (PMID: 15303010). An experimental luciferase-based functional assay has suggested that this variant may reduce LDLR promoter activity significantly, but actual data were not shown (PMID: 15303010). Another experimental functional study using high-throughput screening has shown that this variant causes an approximately 40% repression in promoter activity (PMID: 31395865). To our knowledge, it has not been shown whether this variant results in reduced LDLR expression and function in individuals carrying this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15303010, 35052492; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002312518.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant occurs in a non-coding region of the LDLR gene. It does not change the encoded amino acid sequence of the LDLR protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 15303010). This variant is also known as c.-60C>T. ClinVar contains an entry for this variant (Variation ID: 250944). Studies have shown that this variant alters LDLR gene expression (PMID: 31395865). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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