NM_000527.4(LDLR):c.-139_-130delCTCCCCCTGC AND Familial hypercholesterolemia

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 21, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV001178474.14

Allele description [Variation Report for NM_000527.4(LDLR):c.-139_-130delCTCCCCCTGC]

NM_000527.4(LDLR):c.-139_-130delCTCCCCCTGC

Genes:

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

Variant type:

Deletion

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.4(LDLR):c.-139_-130delCTCCCCCTGC

HGVS:

NC_000019.10:g.11089410_11089419del
NG_009060.1:g.5030_5039del
NM_001195798.1:c.-139_-130delCTCCCCCTGC
NM_001195799.1:c.-139_-130delCTCCCCCTGC
NM_001195800.1:c.-139_-130delCTCCCCCTGC
NM_001195803.1:c.-139_-130delCTCCCCCTGC
LRG_274t1:c.-139_-130del
LRG_274:g.5030_5039del
NC_000019.9:g.11200085_11200094del
NC_000019.9:g.11200086_11200095del
NM_000527.4:c.-139_-130del
NM_000527.4:c.-139_-130delCTCCCCCTGC
NR_163945.1:n.242_251del

Links:

dbSNP: rs2077055015

NCBI 1000 Genomes Browser:

rs2077055015

Molecular consequence:

NR_163945.1:n.242_251del - 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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SCD [Neomonachus schauinslandi]
SCD [Neomonachus schauinslandi]
Gene ID:110589245

Gene
LALBA [Cebus imitator]
LALBA [Cebus imitator]
Gene ID:108316123

Gene
"468088-32-6"[CompleteSynonym] (0)
PubChem Compound
"957242-02-3"[CompleteSynonym] (1)
PubChem Compound
"13573-28-9"[CompleteSynonym] (1)
PubChem Compound

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001342932	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 21, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004318471	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 21, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 29576406, 1301956, 15241806, 18096825, 19007590, 19411563, 21538688, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001342932

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 21, 2019)

germline

clinical testing

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

SCV004318471

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 21, 2024)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Screening of LDLR and APOB gene mutations in Mexican patients with homozygous familial hypercholesterolemia.

Hernández Flores TJ, González García JR, Colima Fausto AG, Vázquez Cárdenas NA, Sánchez López Y, Zarate Morales CA, Magaña Torres MT.

J Clin Lipidol. 2018 May - Jun;12(3):693-701. doi: 10.1016/j.jacl.2018.02.015. Epub 2018 Mar 1.

PubMed [citation]

PMID:: 29576406

See all PubMed Citations (9)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001342932.2

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

Description

This variant deletes 10 nucleotides from the conserved SP1 binding site in the promoter region of the LDLR gene. To our knowledge, functional studies have not been performed for this variant. However, multiple single nucleotide alterations at the conserved residues within the SP1 binding site have been shown to result in a significantly decreased promoter activity (PMID: 25248394) and have been observed in association with disease (Clinvar variation ID: 3745, 250951, 250952, 250955, 250956). This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD), but this variant is located in a low coverage region and its prevalence in the general population is not clear. Based on the available evidence, this variant is classified as Likely Pathogenic.

#	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, SCV004318471.1

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

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. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 29576406; Invitae). ClinVar contains an entry for this variant (Variation ID: 919994). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts the c.-135C nucleotide in the LDLR gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 1301956, 15241806, 18096825, 19007590, 19411563, 21538688). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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: Nov 3, 2024

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