NM_000527.5(LDLR):c.1706-2A>T AND Familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 4, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002229340.6

Allele description [Variation Report for NM_000527.5(LDLR):c.1706-2A>T]

NM_000527.5(LDLR):c.1706-2A>T

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.1706-2A>T

HGVS:

NC_000019.10:g.11116857A>T
NG_009060.1:g.32477A>T
NM_000527.5:c.1706-2A>TMANE SELECT
NM_001195798.2:c.1706-2A>T
NM_001195799.2:c.1583-2A>T
NM_001195800.2:c.1202-2A>T
NM_001195803.2:c.1325-2A>T
LRG_274t1:c.1706-2A>T
LRG_274:g.32477A>T
NC_000019.9:g.11227533A>T
NM_000527.4:c.1706-2A>T
c.1706-2A>T

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001500; dbSNP: rs878854027

NCBI 1000 Genomes Browser:

rs878854027

Molecular consequence:

NM_000527.5:c.1706-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195798.2:c.1706-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195799.2:c.1583-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195800.2:c.1202-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195803.2:c.1325-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV000285017	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 4, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22129472, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000285017

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 4, 2021)

germline

clinical testing

PubMed (2)
[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

The Arabic allele: a single base pair substitution activates a 10-base downstream cryptic splice acceptor site in exon 12 of LDLR and severely decreases LDLR expression in two unrelated Arab families with familial hypercholesterolemia.

Shawar SM, Al-Drees MA, Ramadan AR, Ali NH, Alfadhli SM.

Atherosclerosis. 2012 Feb;220(2):429-36. doi: 10.1016/j.atherosclerosis.2011.10.045. Epub 2011 Nov 9.

PubMed [citation]

PMID:: 22129472

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000285017.6

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

Description

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with a 10 nucleotide deletion in exon 12, which introduces a premature termination codon (PMID: 22129472). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 22129472). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 237865). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 11 of the LDLR gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.

#	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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