NM_000527.5(LDLR):c.818-1G>A AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 6, 2022
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:: RCV002429170.2

Allele description [Variation Report for NM_000527.5(LDLR):c.818-1G>A]

NM_000527.5(LDLR):c.818-1G>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.818-1G>A

HGVS:

NC_000019.10:g.11107391G>A
NG_009060.1:g.23011G>A
NM_000527.5:c.818-1G>AMANE SELECT
NM_001195798.2:c.818-1G>A
NM_001195799.2:c.695-1G>A
NM_001195800.2:c.314-1G>A
NM_001195803.2:c.437-1G>A
LRG_274t1:c.818-1G>A
LRG_274:g.23011G>A
NC_000019.9:g.11218067G>A
NM_000527.4:c.818-1G>A
c.818-1G>A

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000673; dbSNP: rs879254688

NCBI 1000 Genomes Browser:

rs879254688

Molecular consequence:

NM_000527.5:c.818-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195798.2:c.818-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195799.2:c.695-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195800.2:c.314-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195803.2:c.437-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Cophinforma tumefaciens isolate ACCC 35249 internal transcribed spacer 1, partial sequence; 5.8S ribosomal RNA gene and internal transcribed spacer 2, complete sequence; and large subunit ribosomal RNA gene, partial sequence
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002681176	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 6, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16389549, 17935672 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002681176

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 6, 2022)

germline

clinical testing

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing.

Humphries SE, Cranston T, Allen M, Middleton-Price H, Fernandez MC, Senior V, Hawe E, Iversen A, Wray R, Crook MA, Wierzbicki AS.

J Mol Med (Berl). 2006 Mar;84(3):203-14. Epub 2005 Dec 31.

PubMed [citation]

PMID:: 16389549

Two novel mutations of the LDL receptor gene associated with familial hypercholesterolemia in a Chinese family.

Xie L, Gong QH, Xie ZG, Liang ZM, Hu ZM, Xia K, Xia JH, Yang YF.

Chin Med J (Engl). 2007 Oct 5;120(19):1694-9.

PubMed [citation]

PMID:: 17935672

Details of each submission

From Ambry Genetics, SCV002681176.2

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

Description

The c.818-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 6 of the LDLR gene. This alteration has been detected in a familial hypercholesterolemia (FH) cohort (Humphries SE et al. J. Mol. Med., 2006 Mar;84:203-14). It was also reported in the homozygous state in a Chinese male with a homozygous FH phenotype, who was additionally heterozygous for the LDLR p.W165* pathogenic mutation (Xie L et al. Chin. Med. J., 2007 Oct;120:1694-9). A disease-causing mutation impacting the same canonical acceptor splice site, c.818-2A>G, has also been described (Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42). RNA studies for both c.818-1G>A and c.818-2A>G have been reported to cause retention of the same 10 intronic nucleotides between exons 5 and 6, resulting in a frameshift with a predicted alternate stop codon (Xie L et al. Chin. Med. J., 2007 Oct;120:1694-9; Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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