NM_000527.4(LDLR):c.313+1G>A AND Homozygous familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 26, 2019
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:: RCV000844753.6

Allele description [Variation Report for NM_000527.4(LDLR):c.313+1G>A]

NM_000527.4(LDLR):c.313+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_000527.4(LDLR):c.313+1G>A

Other names:

exon 3 skip; FH-Elverum; FH Olbia; IVS3 ds G-A +1

HGVS:

NC_000019.10:g.11102787G>A
NG_009060.1:g.18407G>A
NG_140409.1:g.682G>A
NM_000527.5:c.313+1G>AMANE SELECT
NM_001195798.2:c.313+1G>A
NM_001195799.2:c.191-2433G>A
NM_001195800.2:c.313+1G>A
NM_001195803.2:c.313+1G>A
NM_001406861.1:c.572G>A
NP_001393790.1:p.Arg191His
LRG_274t1:c.313+1G>A
LRG_274:g.18407G>A
NC_000019.9:g.11213463G>A
NM_000527.3:c.313+1G>A
NM_000527.4:c.313+1G>A
NM_000527.5:c.313+1G>A
c.313+1G>A
p.(Leu64_Pro105delinsSer)

Nucleotide change:

IVS3, G-A, +1

Protein change:

R191H

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000045; OMIM: 606945.0054

Molecular consequence:

NM_001195799.2:c.191-2433G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001406861.1:c.572G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_000527.5:c.313+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195798.2:c.313+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195800.2:c.313+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195803.2:c.313+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000271388	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Mar 26, 2019)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 7718019, 10441197, 22883975, 19361455, 10735632, 7749829, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000271388

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Mar 26, 2019)

germline

clinical testing

PubMed (7)
[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	unknown	6	6	not provided	not provided	not provided	clinical testing

Citations

PubMed

Two founder mutations in the LDL receptor gene in Norwegian familial hypercholesterolemia subjects.

Leren TP, Solberg K, Rødningen OK, Tonstad S, Ose L.

Atherosclerosis. 1994 Dec;111(2):175-82.

PubMed [citation]

PMID:: 7718019

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

See all PubMed Citations (7)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000271388.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (7)

Description

The c.313+1G>A variant in LDLR has been reported in >140 individuals with familial hypercholesterolemia (FH) and segregated with disease in at least 5 affected relatives from 2 families (Leren 1994, Sun 1995, Lombardi 2000, Hooper 2012). This variant has also been identified in 7/111670 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. The c.313+1G>A variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing that would preserve the protein reading frame, leading to an abnormal protein. Furthermore, in vitro functional studies provide some evidence that this variant may impact protein function (Sun 1995, Cameron 2009). In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon presence in multiple affected individuals, segregation studies, low frequency in the general population, and impact to the protein. The ACMG/AMP Criteria applied: PS4, PM2, PP1_Moderate, PVS1_Moderate.

#	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		6	not provided	6	not provided

Last Updated: Nov 3, 2024

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