NM_000527.5(LDLR):c.1359-1G>A AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 24, 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:: RCV000775066.18

Allele description [Variation Report for NM_000527.5(LDLR):c.1359-1G>A]

NM_000527.5(LDLR):c.1359-1G>A

Genes:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
MIR6886:microRNA 6886 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.1359-1G>A

Other names:

IVS9 as G-A -1

HGVS:

NC_000019.10:g.11113534G>A
NG_009060.1:g.29154G>A
NM_000527.5:c.1359-1G>AMANE SELECT
NM_001195798.2:c.1359-1G>A
NM_001195799.2:c.1236-1G>A
NM_001195800.2:c.855-1G>A
NM_001195803.2:c.978-1G>A
LRG_274t1:c.1359-1G>A
LRG_274:g.29154G>A
NC_000019.9:g.11224210G>A
NM_000527.4:c.1359-1G>A
NR_106946.1:n.61G>A
c.1359-1G>A

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001405; dbSNP: rs139617694

NCBI 1000 Genomes Browser:

rs139617694

Molecular consequence:

NR_106946.1:n.61G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000527.5:c.1359-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195798.2:c.1359-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195799.2:c.1236-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195800.2:c.855-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195803.2:c.978-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

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

Recent activity

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peroxidase N [Zea mays]
peroxidase N [Zea mays]
gi|670406530|ref|XP_008644819.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000544700	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 24, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 9254862, 10735632, 11668640, 11857755, 15241806, 21382890, 21475731, 22390909, 25154303, 10090473, 28492532
SCV000909167	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 15, 2023)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 7616128, 9254862, 10090473, 10735632, 11668640, 11857755, 12436241, 15241806, 21382890, 21475731, 25154303, 33955087, 34037665, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000544700

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 24, 2023)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV000909167

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 15, 2023)

germline

clinical testing

PubMed (14)
[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

Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29,365 individuals tested for 64 specific low-density lipoprotein-receptor sequence variants.

Huijgen R, Kindt I, Defesche JC, Kastelein JJ.

Eur Heart J. 2012 Sep;33(18):2325-30. doi: 10.1093/eurheartj/ehs038. Epub 2012 Mar 4.

PubMed [citation]

PMID:: 22390909

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (16)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000544700.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change affects an acceptor splice site in intron 9 of the LDLR gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 9254862, 10735632, 11668640, 11857755, 15241806, 21382890, 21475731, 22390909, 25154303). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162499). Studies have shown that disruption of this splice site results in activation of a cryptic acceptor splice site and introduces a premature termination codon (PMID: 10090473). The resulting mRNA is expected to undergo nonsense-mediated decay. 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 Color Diagnostics, LLC DBA Color Health, SCV000909167.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

This variant causes a G to A nucleotide substitution at the -1 position of intron 9 of the LDLR gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A quantitative RNA study has shown that this variant causes a deletion of the first seven nucleotides of exon 10 due to a cryptic splice acceptor activation, and is expected to cause a frameshift and premature truncation (PMID: 10090473). This variant has been reported in hundreds of individuals affected with familial hypercholesterolemia (PMID: 7616128, 9254862, 10090473, 10735632, 11668640, 11857755, 12436241, 15241806, 21382890, 21475731, 25154303, 33955087, 34037665). It has been shown that this variant segregates with disease in multiple affected individuals in two families (PMID: 9254862, 25154303). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is 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

Last Updated: Oct 26, 2024

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