NM_000527.5(LDLR):c.68-1G>C AND Cardiovascular phenotype

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 21, 2018
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:: RCV002365237.1

Allele description

NM_000527.5(LDLR):c.68-1G>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.68-1G>C

HGVS:

NC_000019.10:g.11100222G>C
NG_009060.1:g.15842G>C
NM_000527.5:c.68-1G>CMANE SELECT
NM_001195798.2:c.68-1G>C
NM_001195799.2:c.68-1G>C
NM_001195800.2:c.68-1G>C
NM_001195803.2:c.68-1G>C
NM_001406861.1:c.326-1G>C
LRG_274t1:c.68-1G>C
LRG_274:g.15842G>C
NC_000019.9:g.11210898G>C
NM_000527.4:c.68-1G>C
c.68-1G>C

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001810; dbSNP: rs879254397

NCBI 1000 Genomes Browser:

rs879254397

Molecular consequence:

NM_000527.5:c.68-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195798.2:c.68-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195799.2:c.68-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195800.2:c.68-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195803.2:c.68-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406861.1:c.326-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

Observations:

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002664186	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Jun 21, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10200052, 23375686, 27206942 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002664186

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Jun 21, 2018)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

A novel point mutation in a splice acceptor site of intron 1 of the human low density lipoprotein receptor gene which causes severe hypercholesterolemia: an unexpected absence of exon skipping. Mutations in brief no. 139. Online.

Maruyama T, Miyake Y, Yamamura T, Tajima S, Funahashi T, Matsuzawa Y, Yamamoto A.

Hum Mutat. 1998;11(6):480-1.

PubMed [citation]

PMID:: 10200052

Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.

Bertolini S, Pisciotta L, Rabacchi C, Cefalù AB, Noto D, Fasano T, Signori A, Fresa R, Averna M, Calandra S.

Atherosclerosis. 2013 Apr;227(2):342-8. doi: 10.1016/j.atherosclerosis.2013.01.007. Epub 2013 Jan 19.

PubMed [citation]

PMID:: 23375686

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002664186.1

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

Description

The c.68-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 2 of the LDLR gene, and is located in the region of the ligand binding 1 domain. This variant has been reported in a homozygous Japanese female from consanguineous parents, who had hypercholesterolemia and tendon xanthomas, as well as in an Italian family with heterozygous familial hypercholesterolemia, and in a Japanese female with hypercholesterolemia who also harbored a PCSK9 variant (Maruyama T et al. Hum. Mutat., 1998;11:480-1; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Ohta N et al. J Clin Lipidol 2016 Jan;10:547-555.e5). Limited functional studies in fibroblasts from the homozygous individual reportedly showed no LDLR protein was produced, while RNA studies suggested use of a downstream cryptic acceptor site caused a frameshift leading to a premature stop codon (Maruyama T et al. Hum. Mutat., 1998;11:480-1). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: Feb 20, 2024

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