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NM_000527.5(LDLR):c.1358+2T>A AND Homozygous familial hypercholesterolemia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 29, 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:
RCV000844727.5

Allele description [Variation Report for NM_000527.5(LDLR):c.1358+2T>A]

NM_000527.5(LDLR):c.1358+2T>A

Gene:
LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19p13.2
Genomic location:
Preferred name:
NM_000527.5(LDLR):c.1358+2T>A
HGVS:
  • NC_000019.10:g.11113451T>A
  • NG_009060.1:g.29071T>A
  • NM_000527.5:c.1358+2T>AMANE SELECT
  • NM_001195798.2:c.1358+2T>A
  • NM_001195799.2:c.1235+2T>A
  • NM_001195800.2:c.854+2T>A
  • NM_001195803.2:c.977+2T>A
  • LRG_274t1:c.1358+2T>A
  • LRG_274:g.29071T>A
  • NC_000019.9:g.11224127T>A
  • NM_000527.4:c.1358+2T>A
  • c.1358+2T>A
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000544; dbSNP: rs193922567
NCBI 1000 Genomes Browser:
rs193922567
Molecular consequence:
  • NM_000527.5:c.1358+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195798.2:c.1358+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195799.2:c.1235+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195800.2:c.854+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195803.2:c.977+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000271382Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Mar 29, 2019) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Mutations in the low-density-lipoprotein receptor gene in German patients with familial hypercholesterolaemia.

Weiss N, Binder G, Keller C.

J Inherit Metab Dis. 2000 Dec;23(8):778-90.

PubMed [citation]
PMID:
11196104

Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia.

Nauck MS, Köster W, Dörfer K, Eckes J, Scharnagl H, Gierens H, Nissen H, Nauck MA, Wieland H, März W.

Hum Mutat. 2001 Aug;18(2):165-6.

PubMed [citation]
PMID:
11462246
See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000271382.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

The c.1358+2T>A variant in LDLR has been reported in 2 individuals with familial hypercholesterolemia and segregated with disease in both families (Weiss 2000, Nauck 2001). This variant has also been identified in 1/66288 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs193922567). However, this frequency is low enough to be consistent with the frequency of familial hypercholesterolemia in the general population. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of LDLR function is an established disease mechanism in familial hypercholesterolemia. In summary, this variant meets our criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon the predicted impact to the protein.

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

Last Updated: Nov 10, 2024