NM_000527.4(LDLR):c.694+2T>C AND Familial hypercholesterolemia

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 15, 2020
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:: RCV001201185.1

Allele description

NM_000527.4(LDLR):c.694+2T>C

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.4(LDLR):c.694+2T>C

HGVS:

NC_000019.10:g.11105602T>C
NG_009060.1:g.21222T>C
NM_000527.5:c.694+2T>CMANE SELECT
NM_001195798.2:c.694+2T>C
NM_001195799.2:c.571+2T>C
NM_001195800.2:c.314-1790T>C
NM_001195803.2:c.314-963T>C
LRG_274t1:c.694+2T>C
LRG_274:g.21222T>C
NC_000019.9:g.11216278T>C
NM_000527.4:c.694+2T>C
c.694+2T>C

Nucleotide change:

IVS4, T-C, +2

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000500; OMIM: 606945.0056; dbSNP: rs200238879

NCBI 1000 Genomes Browser:

rs200238879

Molecular consequence:

NM_001195800.2:c.314-1790T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-963T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.694+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195798.2:c.694+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195799.2:c.571+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001372245	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 15, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26802169, 9222758 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001372245

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jun 15, 2020)

germline

clinical testing

PubMed (2)
[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

Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France.

Wintjens R, Bozon D, Belabbas K, MBou F, Girardet JP, Tounian P, Jolly M, Boccara F, Cohen A, Karsenty A, Dubern B, Carel JC, Azar-Kolakez A, Feillet F, Labarthe F, Gorsky AM, Horovitz A, Tamarindi C, Kieffer P, Lienhardt A, Lascols O, Di Filippo M, et al.

J Lipid Res. 2016 Mar;57(3):482-91. doi: 10.1194/jlr.P055699. Epub 2016 Jan 22.

PubMed [citation]

PMID:: 26802169
PMCID:: PMC4766997

Common founder mutation in the LDL receptor gene causing familial hypercholesterolaemia in the Icelandic population.

Gudnason V, Sigurdsson G, Nissen H, Humphries SE.

Hum Mutat. 1997;10(1):36-44.

PubMed [citation]

PMID:: 9222758

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001372245.1

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

Description

Variant summary: LDLR c.694+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. Experimental evidence supports these predictions indicating that this variant causes abnormal mRNA splicing (Gudnason_1997). The variant was absent in 244508 control chromosomes (gnomAD). c.694+2T>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Gudnason_1997, Wintjens_2016). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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: Nov 29, 2022

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