NM_000527.5(LDLR):c.1586+5G>C AND Familial hypercholesterolemia

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Jan 24, 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:: RCV000586202.14

Allele description [Variation Report for NM_000527.5(LDLR):c.1586+5G>C]

NM_000527.5(LDLR):c.1586+5G>C

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.1586+5G>C

HGVS:

NC_000019.10:g.11113767G>C
NG_009060.1:g.29387G>C
NM_000527.5:c.1586+5G>CMANE SELECT
NM_001195798.2:c.1586+5G>C
NM_001195799.2:c.1463+5G>C
NM_001195800.2:c.1082+5G>C
NM_001195803.2:c.1205+5G>C
LRG_274t1:c.1586+5G>C
LRG_274:g.29387G>C
NC_000019.9:g.11224443G>C
NC_000019.9:g.11224443G>C
NM_000527.4(LDLR):c.1586+5G>C
NM_000527.4:c.1586+5G>C

Links:

dbSNP: rs781362878

NCBI 1000 Genomes Browser:

rs781362878

Molecular consequence:

NM_000527.5:c.1586+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195798.2:c.1586+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195799.2:c.1463+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195800.2:c.1082+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.1205+5G>C - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000627020	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 12124988, 17964958, 23680767, 31345425, 17576681, 9536098, 7635461, 10668928, 19208450, 28492532
SCV000697203	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 6, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17964958, 23680767 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001422708	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 22, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 17964958, 25741868 Citation Link,
SCV001460279	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Sep 16, 2020)	germline	clinical testing
SCV005205793	Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham	no assertion criteria provided	Uncertain significance (Jan 1, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17964958, 23680767

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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, curation
Asian- South Indian	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The UMD-LDLR database: additions to the software and 490 new entries to the database.

Villéger L, Abifadel M, Allard D, Rabès JP, Thiart R, Kotze MJ, Béroud C, Junien C, Boileau C, Varret M.

Hum Mutat. 2002 Aug;20(2):81-7. Review.

PubMed [citation]

PMID:: 12124988

Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia.

Trinder M, Li X, DeCastro ML, Cermakova L, Sadananda S, Jackson LM, Azizi H, Mancini GBJ, Francis GA, Frohlich J, Brunham LR.

J Am Coll Cardiol. 2019 Jul 30;74(4):512-522. doi: 10.1016/j.jacc.2019.05.043.

PubMed [citation]

PMID:: 31345425

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000627020.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change falls in intron 10 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has been observed in individuals with hypercholesterolemia (PMID: 12124988, 17964958, 23680767, 31345425; Invitae). ClinVar contains an entry for this variant (Variation ID: 440652). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.1586+5G nucleotide in the LDLR gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 7635461, 10668928, 19208450). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697203.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: c.1586+5G>C affects a conserved nucleotide, resulting in an intronic change. Mutation taster predicts this variant to be disease-causing. 5/5 programs in Alamut predict a loss (or weakening effect) of the canonical splicing donor site and ESE finder predicts changes of binding motifs for RNA splicing enhancers. This variant was not found in 117702 control chromosomes. This variant has been reported in multiple FH pts with evidence of segregation (Yang_JFormosMedAssoc_2008a). Taken together, this variant was classified as Likely Pathogenic until more information becomes available.

#	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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422708.2

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

Description

The c.1586+5G>C variant in LDLR has been reported in at least 2 Taiwanese individuals with familial hypercholesterolemia (PMID: 17964958), and has been identified in 0.02% (4/18384) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs781362878). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as likely pathogenic and pathogenic (Variation ID#: 440652). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine/rule out pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS4 (Richards 2015).

#	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 Natera, Inc., SCV001460279.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	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 Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, SCV005205793.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian- South Indian	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

c.1586+5G>C affects a conserved nucleotide, resulting in an intronic change. Mutation taster predicts this variant to be disease-causing. This variant has been reported in multiple FH pts with evidence of segregation (Yang_JFormosMedAssoc_2008a)

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

Last Updated: Nov 3, 2024

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