NM_000527.5(LDLR):c.313+1G>C AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 30, 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:: RCV002321838.3

Allele description [Variation Report for NM_000527.5(LDLR):c.313+1G>C]

NM_000527.5(LDLR):c.313+1G>C

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.313+1G>C

HGVS:

NC_000019.10:g.11102787G>C
NG_009060.1:g.18407G>C
NG_140409.1:g.682G>C
NM_000527.5:c.313+1G>CMANE SELECT
NM_001195798.2:c.313+1G>C
NM_001195799.2:c.191-2433G>C
NM_001195800.2:c.313+1G>C
NM_001195803.2:c.313+1G>C
NM_001406861.1:c.572G>C
NP_001393790.1:p.Arg191Pro
LRG_274t1:c.313+1G>C
LRG_274:g.18407G>C
NC_000019.9:g.11213463G>C
NM_000527.4(LDLR):c.313+1G>C
NM_000527.4:c.313+1G>C
c.313+1G>C

Protein change:

R191P

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001693; dbSNP: rs112029328

NCBI 1000 Genomes Browser:

rs112029328

Molecular consequence:

NM_001195799.2:c.191-2433G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001406861.1:c.572G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_000527.5:c.313+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195798.2:c.313+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195800.2:c.313+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195803.2:c.313+1G>C - 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
SCV002607712	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jun 30, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10790219, 11668640, 19361455, 7616128, 7718019, 8829662 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002607712

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jun 30, 2023)

germline

clinical testing

PubMed (6)
[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

Mutation analysis in 36 unrelated Spanish subjects with familial hypercholesterolemia: identification of 3 novel mutations in the LDL receptor gene.

Mozas P, Cenarro A, Civeira F, Castillo S, Ros E, Pocovi M.

Hum Mutat. 2000 May;15(5):483-4.

PubMed [citation]

PMID:: 10790219

Molecular genetics of familial hypercholesterolemia in Spain: Ten novel LDLR mutations and population analysis.

García-García AB, Real JT, Puig O, Cebolla E, Marín-García P, Martínez Ferrandis JI, García-Sogo M, Civera M, Ascaso JF, Carmena R, Armengod ME, Chaves FJ.

Hum Mutat. 2001 Nov;18(5):458-9.

PubMed [citation]

PMID:: 11668640

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV002607712.3

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

Description

The c.313+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 3 of the LDLR gene. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in multiple familial hypercholesterolemia (FH) patients (Lombardi P et al. J Lipid Res. 1995;36:860-7; Mozas P et al. Hum Mutat. 2000;15:483-4; García-García AB et al. Hum Mutat. 2001;18:458-9). Two other alterations at the same nucleotide position, c.313+1G>A and c.313+1G>T, have also described in individuals with FH, and were shown to cause aberrant splicing as well as attenuated LDLR gene expression (Leren TP et al. Atherosclerosis. 1994;111:175-82; Jensen HK et al. Hum Mutat. 1996;7:269-71; Cameron J et al. Clin Chim Acta. 2009;403:131-5). This nucleotide position is highly conserved in available vertebrate species. 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: Sep 29, 2024

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