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

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 8, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000586459.10

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:: 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
SCV000544677	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 1301956, 8599353, 9026534, 10447263, 16250003, 28492532
SCV000697246	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 23, 2017)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000544677

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 8, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000697246

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Oct 23, 2017)

germline

clinical testing

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

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

FH Tulsa-1 and -2: two unique alleles for familial hypercholesterolemia presenting in an affected two-year-old African-American male.

Blackett PR, Altmiller DH, Jelley D, Wilson DP.

Am J Med Genet. 1995 Nov 20;59(3):300-3.

PubMed [citation]

PMID:: 8599353

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000544677.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This variant, c.663_683dup, results in the insertion of 7 amino acid(s) of the LDLR protein (p.Asp221_Asp227dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with familial hypercholesterolemia and homozygous familial hypercholesterolemia (PMID: 1301956, 8599353, 9026534, 10447263, 16250003; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 251358). For these reasons, this variant has been 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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697246.2

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

Description

Variant Summary: The c.663_683dupCTGCAAGGACAAATCTGACGA (p.Asp221_Asp227dup) variant is an in-frame duplication of 21 nucleotides and results in the in-frame duplication of 7 codons in a non-repetitive region. Mutation taster predicts benign outcome for this variant. This variant is absent in 275344 control chromosomes (gnomAD). It has been reported in several individuals in the literature with either definite homozygous FH along with a second pathogenic LDLR variant or heterozygous FH. In three publications, patients with homozygous FH were shown to have <2% LDL-r activity (Webb_1996, Hobbs_1992, Blackett_1995). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Other similar variants have been reported in association with FH in database (HGMD). Taken together, this variant is 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: May 1, 2024

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