NM_000527.5(LDLR):c.2108_2114dup (p.Arg706fs) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 4, 2023
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:: RCV004020973.1

Allele description [Variation Report for NM_000527.5(LDLR):c.2108_2114dup (p.Arg706fs)]

NM_000527.5(LDLR):c.2108_2114dup (p.Arg706fs)

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.2108_2114dup (p.Arg706fs)

HGVS:

NC_000019.10:g.11120490_11120496dup
NG_009060.1:g.36110_36116dup
NM_000527.5:c.2108_2114dupMANE SELECT
NM_001195798.2:c.2108_2114dup
NM_001195799.2:c.1985_1991dup
NM_001195800.2:c.1604_1610dup
NM_001195803.2:c.1606+257_1606+263dup
NP_000518.1:p.Arg706fs
NP_000518.1:p.Arg706fs
NP_001182727.1:p.Arg706fs
NP_001182728.1:p.Arg665fs
NP_001182729.1:p.Arg538fs
LRG_274t1:c.2108_2114dup
LRG_274:g.36110_36116dup
LRG_274p1:p.Arg706fs
NC_000019.9:g.11231163_11231164insGCTGCTG
NC_000019.9:g.11231166_11231172dup
NM_000527.4:c.2108_2114dup
NM_000527.4:c.2108_2114dupTGCTGGC
c.2108_2114dup

Protein change:

R538fs

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000675; dbSNP: rs879255141

NCBI 1000 Genomes Browser:

rs879255141

Molecular consequence:

NM_000527.5:c.2108_2114dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195798.2:c.2108_2114dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195799.2:c.1985_1991dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195800.2:c.1604_1610dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195803.2:c.1606+257_1606+263dup - 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
SCV004085715	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 4, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11005141, 29353225 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004085715

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Oct 4, 2023)

germline

clinical testing

PubMed (2)
[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

Low-density lipoprotein receptor gene mutations in a Southeast Asian population with familial hypercholesterolemia.

Khoo KL, van Acker P, Defesche JC, Tan H, van de Kerkhof L, Heijnen-van Eijk SJ, Kastelein JJ, Deslypere JP.

Clin Genet. 2000 Aug;58(2):98-105.

PubMed [citation]

PMID:: 11005141

Spectrum of mutations in index patients with familial hypercholesterolemia in Singapore: Single center study.

Pek SLT, Dissanayake S, Fong JCW, Lin MX, Chan EZL, Tang JI, Lee CW, Ong HY, Sum CF, Lim SC, Tavintharan S.

Atherosclerosis. 2018 Feb;269:106-116. doi: 10.1016/j.atherosclerosis.2017.12.028. Epub 2017 Dec 27.

PubMed [citation]

PMID:: 29353225

Details of each submission

From Ambry Genetics, SCV004085715.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.2108_2114dupTGCTGGC pathogenic mutation, located in coding exon 14 of the LDLR gene, results from a duplication of TGCTGGC at nucleotide position 2108, causing a translational frameshift with a predicted alternate stop codon (p.R706Afs*13). This alteration has been reported in multiple individuals with either a clinical diagnosis of familial hypercholesterolemia (FH) or a probable diagnosis of FH (Pek SLT et al. Atherosclerosis, 2018 Feb;269:106-116; Khoo KL et al. Clin Genet, 2000 Aug;58:98-105). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, 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: Nov 3, 2024

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