rs875989916

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000527.5(LDLR):c.1118_1121dup(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 (★★). 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:15

Conservation

PhyloP100: -0.0530

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 [Likely_pathogenic]. Clinvar id is 226347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.1118_1121dup	p.Tyr375TrpfsTer7	frameshift_variant	8/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1118_1121dup	p.Tyr375TrpfsTer7	frameshift_variant	8/18	1	NM_000527.5	P3	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

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251364

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135888

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 31, 2019	The c.1118_1121dupGTGG (p.Tyr375Trpfs7) 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.Tyr375Trpfs7) variant of LDLR gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Jun 05, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1988	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jan 31, 2012	- -

Familial hypercholesterolemia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 03, 2023	This sequence change creates a premature translational stop signal (p.Tyr375Trpfs7) 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). This variant is also known as FH Nashville and p.Tyr352fs7. ClinVar contains an entry for this variant (Variation ID: 226347). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 10, 2022	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. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 02, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2022	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) -

Homozygous familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 13, 2018

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2022

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

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over