NM_000527.5(LDLR):c.1359-1G>A AND Homozygous familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 23, 2015
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:: RCV000844728.12

Allele description [Variation Report for NM_000527.5(LDLR):c.1359-1G>A]

NM_000527.5(LDLR):c.1359-1G>A

Genes:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
MIR6886:microRNA 6886 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.1359-1G>A

Other names:

IVS9 as G-A -1

HGVS:

NC_000019.10:g.11113534G>A
NG_009060.1:g.29154G>A
NM_000527.5:c.1359-1G>AMANE SELECT
NM_001195798.2:c.1359-1G>A
NM_001195799.2:c.1236-1G>A
NM_001195800.2:c.855-1G>A
NM_001195803.2:c.978-1G>A
LRG_274t1:c.1359-1G>A
LRG_274:g.29154G>A
NC_000019.9:g.11224210G>A
NM_000527.4:c.1359-1G>A
NR_106946.1:n.61G>A
c.1359-1G>A

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001405; dbSNP: rs139617694

NCBI 1000 Genomes Browser:

rs139617694

Molecular consequence:

NR_106946.1:n.61G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000527.5:c.1359-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195798.2:c.1359-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195799.2:c.1236-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195800.2:c.855-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195803.2:c.978-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

Observations:

Condition(s)

Name:: Homozygous familial hypercholesterolemia
Synonyms:: Familial hypercholesterolemia - homozygous
Identifiers:: MONDO: MONDO:0018328; MedGen: C0342881

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000271383	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Dec 23, 2015)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 10441197, 25525159, 25637381, 11668640, 7616128, 10735632, 10090473, 22390909, 19208450, 26036859, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000271383

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Dec 23, 2015)

germline

clinical testing

PubMed (11)
[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	not provided	2	2	not provided	not provided	not provided	clinical testing

Citations

PubMed

Intronic mutations at splice junctions in the low-density lipoprotein receptor gene.

Peeters AV, Thiart R, de Villiers JN, Jensen HK, Van Gaal LF, Kotze MJ.

Mol Cell Probes. 1999 Aug;13(4):257-60.

PubMed [citation]

PMID:: 10441197

RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.

Xiong HY, Alipanahi B, Lee LJ, Bretschneider H, Merico D, Yuen RK, Hua Y, Gueroussov S, Najafabadi HS, Hughes TR, Morris Q, Barash Y, Krainer AR, Jojic N, Scherer SW, Blencowe BJ, Frey BJ.

Science. 2015 Jan 9;347(6218):1254806. doi: 10.1126/science.1254806. Epub 2014 Dec 18.

PubMed [citation]

PMID:: 25525159
PMCID:: PMC4362528

See all PubMed Citations (11)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000271383.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (11)

Description

The c.1359-1G>A variant in LDLR has been reported in >80 individuals with famili al hypercholesterolemia (FH), segregated with disease in 8 affected relatives fr om 3 families (Peeters 1995, Lombarid 1995 and 2000, Garcia-Garcia 2001, Braenne 2015), and has been identified in 1/8600 European American chromosomes by the N HLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs139617 694). This variant occurs in the invariant region (+/- 1,2) of the splice consen sus sequence and is predicted to cause altered splicing leading to an abnormal o r absent protein. Heterozygous loss of LDLR function is an established disease m echanism in familial hypercholesterolemia. In summary, this variant meets our cr iteria to be classified as pathogenic for familial hypercholesterolemia in an au tosomal dominant manner. ACMG/AMP criteria applied: PVS1, PP1_S, PS4, PM2 (Richa rds 2015).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	2	not provided

Last Updated: May 12, 2024

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