NM_000527.5(LDLR):c.1118_1121dup (p.Tyr375fs) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (9 submissions)
Last evaluated:: Aug 5, 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:: RCV000211651.16

Allele description [Variation Report for NM_000527.5(LDLR):c.1118_1121dup (p.Tyr375fs)]

NM_000527.5(LDLR):c.1118_1121dup (p.Tyr375fs)

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.1118_1121dup (p.Tyr375fs)

Other names:

FH Nashville; NM_000527.4:c.1121_1122insGTGG; p.Tyr375TrpfsX7

HGVS:

NC_000019.10:g.11111571_11111574dup
NG_009060.1:g.27191_27194dup
NM_000527.5:c.1118_1121dupMANE SELECT
NM_001195798.2:c.1118_1121dup
NM_001195799.2:c.995_998dup
NM_001195800.2:c.614_617dup
NM_001195803.2:c.737_740dup
NP_000518.1:p.Tyr375fs
NP_001182727.1:p.Tyr375fs
NP_001182728.1:p.Tyr334fs
NP_001182729.1:p.Tyr207fs
NP_001182732.1:p.Tyr248fs
LRG_274:g.27191_27194dup
NC_000019.9:g.11222244_11222245insGGGT
NC_000019.9:g.11222247_11222250dup
NC_000019.9:g.11222250_11222251insGTGG
NM_000527.4:c.1118_1121dupGTGG
c.1118_1121dup

Protein change:

Y207fs

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000161; OMIM: 606945.0020; dbSNP: rs875989916

NCBI 1000 Genomes Browser:

rs875989916

Molecular consequence:

NM_000527.5:c.1118_1121dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195798.2:c.1118_1121dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195799.2:c.995_998dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195800.2:c.614_617dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195803.2:c.737_740dup - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024046	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 1988)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000268600	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Jan 31, 2012)	germline	clinical testing
SCV000295228	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Pathogenic (Mar 25, 2016)	germline	literature only	PubMed (4) [See all records that cite these PMIDs] 2088165, 9259195, 22881376, 16389549 Citation Link,
SCV000599361	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2016)	germline, not applicable	curation, literature only	PubMed (2) [See all records that cite these PMIDs] 25741868, 1301956
SCV000782908	Robarts Research Institute, Western University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 2, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001432544	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 5, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV001754785	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003827158	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 15, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005427589	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 5, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 1301956, 23375686, 23680767, 24075752, 26748104, 28964736, 33418990, 34363016, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	not provided	not provided	143475	not provided	clinical testing, curation
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	6	not provided	not provided	5	not provided	clinical testing, literature only, research

Citations

PubMed

Deletion in the first cysteine-rich repeat of low density lipoprotein receptor impairs its transport but not lipoprotein binding in fibroblasts from a subject with familial hypercholesterolemia.

Leitersdorf E, Hobbs HH, Fourie AM, Jacobs M, van der Westhuyzen DR, Coetzee GA.

Proc Natl Acad Sci U S A. 1988 Nov;85(21):7912-6.

PubMed [citation]

PMID:: 3263645
PMCID:: PMC282319

The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein.

Hobbs HH, Russell DW, Brown MS, Goldstein JL.

Annu Rev Genet. 1990;24:133-70. Review. No abstract available.

PubMed [citation]

PMID:: 2088165

See all PubMed Citations (15)

Details of each submission

From OMIM, SCV000024046.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In an American patient with FH (FHCL1; 143890), Leitersdorf and Hobbs (1990) found insertion of 4 nucleotides in exon 8 causing frameshift and premature termination as the basis of this null allele.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268600.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From LDLR-LOVD, British Heart Foundation, SCV000295228.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (4)
2	not provided	1	not provided	not provided	literature only	PubMed (4)
3	not provided	1	not provided	not provided	literature only	PubMed (4)
4	not provided	1	not provided	not provided	literature only	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
4	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000599361.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)
2	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

"Assay Description:Hmz patients' fibroblasts, 125I-LDL assays"

PubMed [ID: 1301956]

#	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
2	not applicable	not applicable	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Robarts Research Institute, Western University, SCV000782908.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia, SCV001432544.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV001754785.1

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

Description

The c.1118_1121dupGTGG (p.Tyr375Trpfs*7) variant in exon 8 of LDLR gene creates a frameshift and an early stop codon which is predicted to result in an absence of protein product. Loss-of-function variants of LDLR gene are known to cause familial hypercholesterolemia (PMID: 20809525). This variant has been reported in multiple unrelated individuals and families with familial hypercholesterolemia (PMID:301956, 9259195, 16389549, 24075752), but only once in general population database gnomAD. Functional assay of this variant demonstrated that only less than 2% of receptor activity was retained compared to wild type protein (PMID: 1301956). Therefore, the c.1118_1121dupGTGG (p.Tyr375Trpfs*7) variant of LDLR gene 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 Revvity Omics, Revvity, SCV003827158.2

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

#	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 All of Us Research Program, National Institutes of Health, SCV005427589.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (9)

Description

The c.1118_1121dup (p.Tyr375Trpfs*7) variant in the LDLR gene is located on the exon 8 and is predicted to result in shift of reading frame that introduces a premature translation termination codon (p.Tyr375Trpfs*7), resulting in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 23375686, 33418990, 26748104). This variant has been identified in 4 unrelated individuals with familial hypercholesterolemia (PMID: 28964736, 23680767, 24075752, 34363016). Experimental study with the homozygous patient cells proved the defective LDLR activity (<2%) (PMID: 1301956). The variant has been reported in ClinVar as pathogenic (ID: 226347). The variant is rare in the general population according to gnomAD (1/251364). Therefore, the c.1118_1121dup (p.Tyr375Trpfs*7) variant of LDLR has been classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	143475	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Mar 16, 2025

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