NM_000527.5(LDLR):c.1586+1G>A AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 9, 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:: RCV001290569.5

Allele description [Variation Report for NM_000527.5(LDLR):c.1586+1G>A]

NM_000527.5(LDLR):c.1586+1G>A

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+1G>A

Other names:

FH Agrigento

HGVS:

NC_000019.10:g.11113763G>A
NG_009060.1:g.29383G>A
NM_000527.5:c.1586+1G>AMANE SELECT
NM_001195798.2:c.1586+1G>A
NM_001195799.2:c.1463+1G>A
NM_001195800.2:c.1082+1G>A
NM_001195803.2:c.1205+1G>A
LRG_274t1:c.1586+1G>A
LRG_274:g.29383G>A
NC_000019.9:g.11224439G>A
NM_000527.4:c.1586+1G>A
c.1586+1G>A
p.(Thr454_Gly529del)andp.(Gly529_Phe530ins22)

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001460;

Molecular consequence:

NM_000527.5:c.1586+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195798.2:c.1586+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195799.2:c.1463+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195800.2:c.1082+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195803.2:c.1205+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV001478645	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 28, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23375686, 32331935 Citation Link,
SCV002230028	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 9, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 16199547, 20809525, 28645073, 9974426, 23375686, 30710474, 31491741, 35339733, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001478645

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jan 28, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV002230028

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 9, 2023)

germline

clinical testing

PubMed (9)
[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

A catalog of the pathogenic mutations of LDL receptor gene in Japanese familial hypercholesterolemia.

Tada H, Hori M, Nomura A, Hosomichi K, Nohara A, Kawashiri MA, Harada-Shiba M.

J Clin Lipidol. 2020 May - Jun;14(3):346-351.e9. doi: 10.1016/j.jacl.2020.03.002. Epub 2020 Mar 24.

PubMed [citation]

PMID:: 32331935

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (10)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001478645.1

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

Description

Variant summary: LDLR c.1586+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251100 control chromosomes. c.1586+1G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Bertolini_2013, Tada_2020). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002230028.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change affects a donor splice site in intron 10 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 9974426). ClinVar contains an entry for this variant (Variation ID: 251905). This variant is also known as g>a+1 (ln 10). Disruption of this splice site has been observed in individuals with hypercholesterolemia (PMID: 9974426, 23375686, 30710474, 31491741, 35339733). This variant is present in population databases (rs755389753, gnomAD 0.0009%).

#	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: Sep 29, 2024

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