NM_000527.5(LDLR):c.1586+1G>A AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 18, 2023
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:: RCV002401937.3

Allele description [Variation Report for NM_000527.5(LDLR):c.1586+1G>A]

NM_000527.5(LDLR):c.1586+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.1586+1G>A

Other names:

FH Agrigento

HGVS:

NC_000019.10:g.11113763G>A
NG_009060.1:g.29383G>A
NM_000527.5:c.1586+1G>AMANE SELECT
NM_001195798.2:c.1586+1G>A
NM_001195799.2:c.1463+1G>A
NM_001195800.2:c.1082+1G>A
NM_001195803.2:c.1205+1G>A
LRG_274t1:c.1586+1G>A
LRG_274:g.29383G>A
NC_000019.9:g.11224439G>A
NM_000527.4:c.1586+1G>A
c.1586+1G>A
p.(Thr454_Gly529del)andp.(Gly529_Phe530ins22)

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001460;

Molecular consequence:

NM_000527.5:c.1586+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195798.2:c.1586+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195799.2:c.1463+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195800.2:c.1082+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195803.2:c.1205+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV002705979	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 18, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9974426, 11317362, 20045108 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002705979

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 18, 2023)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Analysis of LDL receptor gene mutations in Italian patients with homozygous familial hypercholesterolemia.

Bertolini S, Cassanelli S, Garuti R, Ghisellini M, Simone ML, Rolleri M, Masturzo P, Calandra S.

Arterioscler Thromb Vasc Biol. 1999 Feb;19(2):408-18.

PubMed [citation]

PMID:: 9974426

LDL receptor cDNA sequence analysis in familial hypercholesterolemia patients: 5 novel mutations with high prevalence in families originating from southern Italy.

Liguori R, Bianco AM, Argiriou A, Pauciullo P, Giannino A, Rubba P, De Simone V.

Hum Mutat. 2001 May;17(5):433.

PubMed [citation]

PMID:: 11317362

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002705979.3

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

Description

The c.1586+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 10 of the LDLR gene. 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 data from gnomAD, the A allele has an overall frequency of <0.001% (1/251100) total alleles studied. The highest observed frequency was 0.001% (1/113504) of European (non-Finnish) alleles. This alteration, first reported as FH Agrigento (g>a+1 In 10), was detected in the homozygous state in a child from a familial hypercholesterolemia (FH) cohort who had elevated LDL cholesterol, coronary artery disease, aortic stenosis, and <3% LDL receptor activity in fibroblasts (Bertolini, 1999). This alteration has also been detected in other FH cohorts (Liguori, 2001; Romano, 2010). This nucleotide position is highly conserved in available vertebrate species. This alteration was reported to result in abnormal splicing, leading to two abnormal mRNA products, one with an in-frame insertion of 22 amino acids, and one with an in-frame deletion of 76 amino acids in the epidermal growth factor precursor homology domain (Bertolini, 1999). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration 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: Sep 29, 2024

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