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

Clinical significance:Pathogenic (Last evaluated: Jun 15, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_000527.4(LDLR):c.694+2T>C]


LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • 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
LDLR-LOVD, British Heart Foundation: LDLR_000500; OMIM: 606945.0056; dbSNP: rs200238879
NCBI 1000 Genomes Browser:
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]


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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV001372245Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
(Jun 15, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



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]

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]

Details of each submission

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)


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.

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

Last Updated: Nov 27, 2021

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