NM_000527.5(LDLR):c.1845+1G>C AND Familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 23, 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:: RCV001857830.6

Allele description [Variation Report for NM_000527.5(LDLR):c.1845+1G>C]

NM_000527.5(LDLR):c.1845+1G>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.1845+1G>C

HGVS:

NC_000019.10:g.11116999G>C
NG_009060.1:g.32619G>C
NM_000527.5:c.1845+1G>CMANE SELECT
NM_001195798.2:c.1845+1G>C
NM_001195799.2:c.1722+1G>C
NM_001195800.2:c.1341+1G>C
NM_001195803.2:c.1464+1G>C
LRG_274t1:c.1845+1G>C
LRG_274:g.32619G>C
NC_000019.9:g.11227675G>C
NM_000527.4:c.1845+1G>C
c.1845+1G>C

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000763;

Molecular consequence:

NM_000527.5:c.1845+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195798.2:c.1845+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195799.2:c.1722+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195800.2:c.1341+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195803.2:c.1464+1G>C - 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
SCV002131977	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 23, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10790219, 21990180, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002131977

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 23, 2021)

germline

clinical testing

PubMed (3)
[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

Mutation analysis in 36 unrelated Spanish subjects with familial hypercholesterolemia: identification of 3 novel mutations in the LDL receptor gene.

Mozas P, Cenarro A, Civeira F, Castillo S, Ros E, Pocovi M.

Hum Mutat. 2000 May;15(5):483-4.

PubMed [citation]

PMID:: 10790219

Functional characterization of splicing and ligand-binding domain variants in the LDL receptor.

Etxebarria A, Palacios L, Stef M, Tejedor D, Uribe KB, Oleaga A, Irigoyen L, Torres B, Ostolaza H, Martin C.

Hum Mutat. 2012 Jan;33(1):232-43. doi: 10.1002/humu.21630. Epub 2011 Nov 3.

PubMed [citation]

PMID:: 21990180

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002131977.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with retention of intron 12, which introduces a premature termination codon (PMID: 21990180). The resulting mRNA is expected to undergo nonsense-mediated decay. Studies have shown that this variant alters LDLR gene expression (PMID: 21990180). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 10790219, 21990180). ClinVar contains an entry for this variant (Variation ID: 252068). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 12 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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