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NM_000527.5(LDLR):c.663_683dup (p.Asp221_Asp227dup) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 24, 2022
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:
RCV002365241.2

Allele description [Variation Report for NM_000527.5(LDLR):c.663_683dup (p.Asp221_Asp227dup)]

NM_000527.5(LDLR):c.663_683dup (p.Asp221_Asp227dup)

Gene:
LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
19p13.2
Genomic location:
Preferred name:
NM_000527.5(LDLR):c.663_683dup (p.Asp221_Asp227dup)
Other names:
FH Tulsa-1
HGVS:
  • NC_000019.10:g.11105569_11105589dup
  • NG_009060.1:g.21189_21209dup
  • NM_000527.5:c.663_683dupMANE SELECT
  • NM_001195798.2:c.663_683dup
  • NM_001195799.2:c.540_560dup
  • NM_001195800.2:c.314-1823_314-1803dup
  • NM_001195803.2:c.314-996_314-976dup
  • NP_000518.1:p.Asp221_Asp227dup
  • NP_001182727.1:p.Asp221_Asp227dup
  • NP_001182728.1:p.Asp180_Asp186dup
  • LRG_274:g.21189_21209dup
  • NC_000019.9:g.11216241_11216242insCGACTGCAAGGACAAATCTGA
  • NC_000019.9:g.11216245_11216265dup
  • NM_000527.4:c.663_683dup21
  • NM_000527.4:c.663_683dupCTGCAAGGACAAATCTGACGA
  • c.663_683dup
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001249; dbSNP: rs879254620
NCBI 1000 Genomes Browser:
rs879254620
Molecular consequence:
  • NM_000527.5:c.663_683dup - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001195798.2:c.663_683dup - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001195799.2:c.540_560dup - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001195800.2:c.314-1823_314-1803dup - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-996_314-976dup - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002661892Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Pathogenic
(Mar 24, 2022)
germlineclinical testing

PubMed (5)
[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

Citations

PubMed

Identification of recurrent and novel mutations in the LDL receptor gene in Japanese familial hypercholesterolemia. Mutation in brief no. 248. Online.

Hattori H, Nagano M, Iwata F, Homma Y, Egashira T, Okada T.

Hum Mutat. 1999;14(1):87.

PubMed [citation]
PMID:
10447263

Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]
PMID:
1301956
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV002661892.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

The c.663_683dup21 pathogenic mutation (also known as p.D221_D227dup), located in coding exon 4 of the LDLR gene, results from an in-frame duplication of 21 nucleotides at nucleotide positions 663 to 683. This results in the duplication of seven residues (DCKDKSD) between amino acids 221 and 227. This variant, also known as FH Tulsa-1, has been detected in individuals with homozygous familial hypercholesterolemia (FH), who had a second variant in LDLR and attenuated LDLR activity in fibroblasts (Hobbs HH et al. Hum Mutat. 1992;1:445-66; Webb JC et al. J Lipid Res. 1996;37:368-81; Blackett PR, Am. J. Med. Genet. 1995 Nov;59(3):300-3). This variant was reported to segregate with FH in the mother and maternal grandmother of one proband (Webb JC et al. J Lipid Res. 1996;37:368-81). In addition, this variant has been identified in cohorts of FH patients from various ethnic groups and additional individuals with LDL-C levels consistent with FH (Hattori H et al. Hum Mutat. 1999;14:87; Fouchier SW et al. Hum Mutat. 2005;26:550-6; Ambry internal data). This alteration impacts residues in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 5 (Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: Oct 8, 2024