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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002661892	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 24, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10447263, 1301956, 16250003, 8599353, 9026534 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002661892

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Mar 24, 2022)

germline

clinical testing

PubMed (5)
[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

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	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: Oct 8, 2024

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