rs875989916

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000527.5(LDLR):c.1118_1121dupGTGG(p.Tyr375TrpfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,712 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G374G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LDLR
NM_000527.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: -0.0530

Publications

4 publications found

Variant links:

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

LDLR Gene-Disease associations (from GenCC):

hypercholesterolemia, familial, 1
Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LDLR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-11111568-A-AGGGT is Pathogenic according to our data. Variant chr19-11111568-A-AGGGT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 226347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.1118_1121dupGTGG	p.Tyr375TrpfsTer7	frameshift_variant	Exon 8 of 18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.1118_1121dupGTGG	p.Tyr375TrpfsTer7	frameshift_variant	Exon 8 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251364

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461550

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727100

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111820

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:9

Jun 05, 2019

Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Jan 31, 2012

Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation;literature only

- -

Jun 15, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 02, 2018

Robarts Research Institute, Western University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 05, 2024

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Nov 01, 1988

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 31, 2019

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Familial hypercholesterolemia

Pathogenic:4

Feb 15, 2020

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LDLR c.1118_1121dupGTGG (p.Tyr375TrpfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251364 control chromosomes. c.1118_1121dupGTGG has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (example, Faiz_2013, Vandrovcova_2013, Heath_1999). These data indicate that the variant is likely to be associated with disease. No experimental evidence demonstrating an impact on protein function was ascertained. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Tyr375Trpfs*7) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 1301956, 20809525, 24075752). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as FH Nashville and p.Tyr352fs*7. ClinVar contains an entry for this variant (Variation ID: 226347). For these reasons, this variant has been classified as Pathogenic. -

Oct 10, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant (also known as FH Nashville in literature) inserts 4 nucleotides in exon 8 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. Cells from a homozygous individual have shown largely reduced (<2% of wild type) LDLR activity (PMID: 1301956). This variant has been reported in at least 6 unrelated individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 28964736, 34297352). This variant has been identified in 1/251364 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. -

Mar 12, 2025

GENinCode PLC

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1118_1121dup p.(Tyr375TrpfsTer7) variant in LDLR is a frameshift variant predicted to create a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008797 in European (non-Finnish) population, which is lower than the ClinGen FH VCEP threshold (<0.0002) so PM2_MODERATE is met. This variant has been seen in FH patients meeting clinical criteria (PS4_SUPPORTING; PMIDs 16389549, 23680767, 24075752, internal data). Based on the evidence listed above, we have classified this variant as Pathogenic. -

not provided

Pathogenic:3

Sep 14, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Also known as FH Nashville, 11189 insGTGG*, c.1121_1122insGTGG, p.G353fs; This variant is associated with the following publications: (PMID: 31447099, 34040191, 32719484, 32041611, 22881376, 33303402, 2088165, 9259195, 16389549, 23680767, 31345425, 34037665, 24075752, 10208479, 26582918, 1301956) -

Aug 02, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The LDLR c.1118_1121dup (p.Tyr375Trpfs*7) variant (also known as FH Nashville) variant alters the translational reading frame of the LDLR mRNA and causes the premature termination of LDLR protein synthesis. The frequency of this variant in the general population, 0.0000088 (1/113680 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in multiple individuals affected with familial hypercholesteremia (PMIDs: 28964736 (2017), 32041611 (2020), 31345425 (2019), 24075752 (2013), 23680767 (2013), 16389549 (2006), 9259195 (1997), 1301956 (1992)). Based on the available information, this variant is classified as pathogenic. -

Jun 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The LDLR c.1118_1121dup; p.Tyr375TrpfsTer7 variant (rs875989916, ClinVar Variation ID: 226347), also known as FH Nashville, is reported in multiple individuals with familial hypercholesterolemia (Defesche 2017, Hobbs 1992, Murdock 2021, Trinder 2019). This variant is only found on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by inserting four nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Defesche JC et al. Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia. J Clin Lipidol. 2017 Nov-Dec;11(6):1338-1346.e7. PMID: 28964736. Hobbs HH et al. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1992;1(6):445-66. PMID: 1301956. Murdock DR et al. Genetic testing in ambulatory cardiology clinics reveals high rate of findings with clinical management implications. Genet Med. 2021 Dec;23(12):2404-2414. PMID: 34363016. Trinder M et al. Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia. J Am Coll Cardiol. 2019 Jul 30;74(4):512-522. PMID: 31345425. -

Homozygous familial hypercholesterolemia

Pathogenic:1

Feb 13, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Tyr375fs variant has been reported in at least 5 individuals with familial hypercholesterolemia (FH), 4 in the heterozygous state (Day 1997, Humphries 200 6) and 1 in the homozygous state (Hobbs 1992). This variant has also been report ed in ClinVar (Variation ID: 226347). In vitro functional studies provide some e vidence that the p.Tyr375fs variant may impact protein function, resulting in r eceptor activity that <2% compared to wildtype (Hobbs 1992). It has been identif ied in 1/111670 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs875989916). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 375 and leads to a premature termination codon 7 amino acids downst ream. This alteration is then predicted to lead to a truncated or absent protein . Heterozygous loss of function of the LDLR gene is an established disease mecha nism in individuals with FH. In summary, this variant meets criteria to be class ified as pathogenic for FH in an autosomal dominant manner based upon the presen ce in multiple affected individuals, functional evidence, very low frequency in the general population and the predicted impact to the protein. ACMG/AMP Criteri a applied (Richards 2015): PVS1, PM2, PS4_Moderate, PS3_Supporting. -

Cardiovascular phenotype

Pathogenic:1

Feb 16, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1118_1121dupGTGG pathogenic mutation, located in coding exon 8 of the LDLR gene, results from a duplication of 4 nucleotides at positions 1118 to 1121, causing a translational frameshift with a predicted alternate stop codon (p.Y375Wfs*7). This duplication has been reported in several individuals presenting with familial hypercholesterolemia (Hobbs HH et al. Annu Rev Genet. 1990;24:133-70; Tosi I et al. Atherosclerosis 2007;194:102-11; Faiz F et al. Atherosclerosis. 2013;230(2):249-55; Defesche JC et al. J Clin Lipidol Sep;11:1338-1346.e7). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.053

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over