NM_000527.5(LDLR):c.2061dup (p.Asn688fs) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 18, 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:: RCV000781503.9

Allele description [Variation Report for NM_000527.5(LDLR):c.2061dup (p.Asn688fs)]

NM_000527.5(LDLR):c.2061dup (p.Asn688fs)

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.2061dup (p.Asn688fs)

Other names:

N688QfsX29

HGVS:

NC_000019.10:g.11120443dup
NG_009060.1:g.36063dup
NM_000527.5:c.2061dupMANE SELECT
NM_001195798.2:c.2061dup
NM_001195799.2:c.1938dup
NM_001195800.2:c.1557dup
NM_001195803.2:c.1606+210dup
NP_000518.1:p.Asn688fs
NP_001182727.1:p.Asn688fs
NP_001182728.1:p.Asn647fs
NP_001182729.1:p.Asn520fs
LRG_274:g.36063dup
NC_000019.9:g.11231118_11231119insC
NC_000019.9:g.11231119dup
NM_000527.3:c.2061dup
NM_000527.4:c.2061dupC
c.2061dupC
p.Asn688GlnfsX29

Protein change:

N520fs

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001158; dbSNP: rs137853965

NCBI 1000 Genomes Browser:

rs137853965

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
SCV000752425	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 18, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 20809525, 28645073, 16159606, 16389549, 17539906, 22883975, 26046366, 27680772, 28492532
SCV000919584	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 27, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27680772, 16159606, 16389549 Citation Link,
SCV001435012	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 15, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001733660	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 8, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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 spectrum of autosomal dominant hypercholesterolemia in France.

Marduel M, Carrié A, Sassolas A, Devillers M, Carreau V, Di Filippo M, Erlich D, Abifadel M, Marques-Pinheiro A, Munnich A, Junien C; French ADH Research Network., Boileau C, Varret M, Rabès JP.

Hum Mutat. 2010 Nov;31(11):E1811-24. doi: 10.1002/humu.21348.

PubMed [citation]

PMID:: 20809525
PMCID:: PMC3152176

Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene.

Jiang L, Benito-Vicente A, Tang L, Etxebarria A, Cui W, Uribe KB, Pan XD, Ostolaza H, Yang SW, Zhou YJ, Martin C, Wang LY.

Atherosclerosis. 2017 Aug;263:163-170. doi: 10.1016/j.atherosclerosis.2017.06.014. Epub 2017 Jun 8.

PubMed [citation]

PMID:: 28645073

See all PubMed Citations (10)

Details of each submission

From Invitae, SCV000752425.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change creates a premature translational stop signal (p.Asn688Glnfs*29) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is present in population databases (rs751228587, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 16159606, 16389549, 17539906, 22883975, 26046366, 27680772). ClinVar contains an entry for this variant (Variation ID: 68103). 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, SCV000919584.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: The LDLR c.2061dupC (p.Asn688GlnfsX29) variant results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/246074 control chromosomes (in gnomAD) at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). The variant was reported in several individuals affected by definite FH (Graham 2005, Humphries 2006, Martin 2016) In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. 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

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV001435012.1

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

Description

This c.2061dupC (p.Asn688Glnfs*29) variant in exon 14 of the LDLR gene results in an early stop codon. Loss of functions mutations in the LDLR gene are known to be a disease-causing mechanism. This variant has been reported in one patient with familial hypercholesterolaemia (PMID: 16389549). It has been reported at low allelic frequencies in the population database gnomAD (http://gnomad.broadinstitute.org/variant/19-11231118-T-TC). Therefore, the c.2061dupC (p.Asn688Glnfs*29) variant in the LDLR gene has been classified as a pathogenic variant.

#	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 Color Diagnostics, LLC DBA Color Health, SCV001733660.1

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

Description

This variant inserts one nucleotide in exon 14 of the LDLR gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 16159606, 16389549, 17539906, 22883975, 26046366, 27680772). This variant has been identified in 1/251240 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, 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: Jun 23, 2024

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