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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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002705979Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Sep 18, 2023) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024