rs137853966

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.653delG(p.Gly218ValfsTer47) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000685 in 1,459,014 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: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 4.16

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 19-11105557-TG-T is Pathogenic according to our data. Variant chr19-11105557-TG-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 68100.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.653delG	p.Gly218ValfsTer47	frameshift_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.653delG	p.Gly218ValfsTer47	frameshift_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459014

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725588

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33432

American (AMR)

AF:

0.00

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39566

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110544

Other (OTH)

AF:

0.00

AC:

AN:

60224

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypercholesterolemia

Pathogenic:3

Jul 30, 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.Gly218Valfs*47) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypercholesterolemia (PMID: 7649546, 27765764). ClinVar contains an entry for this variant (Variation ID: 68100). For these reasons, this variant has been classified as Pathogenic. -

Apr 30, 2021

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant deletes 1 nucleotide in exon 4 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. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 7649546, 11668627, 19602640, 26046366). This variant has not been identified 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. -

May 16, 2024

GENinCode PLC

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.653del p.(Gly218ValfsTer47) 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). This variant is absent from gnomAD v2.1.1, so PM2_MODERATE is met. This variant has been seen in FH patients meeting clinical criteria (PS4_SUPPORTING; PMIDs 11668627, 35222550). Based on the evidence listed above, we have classified this variant as Pathogenic. -

not provided

Pathogenic:2Other:1

Nov 08, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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; Not observed at significant frequency in large population cohorts (gnomAD); Also reported as 1 bp deletion: G in codon 197, 652delG, and G197V->X243 due to alternate nomenclature; This variant is associated with the following publications: (PMID: 7649546, 11668627, 27765764, 34040191, 34037665, 35222550, 1301956, 9259195, 19602640) -

SNPedia

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

May 07, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This frameshift variant causes the premature termination of LDLR protein synthesis. It has been reported in multiple individuals and families affected with hypercholesterolemia in the published literature (PMID: 7649546 (1995), 11668627 (2001), 19602640 (2009), 27765764 (2016)). Therefore, the variant is classified as pathogenic. -

Hypercholesterolemia, familial, 1

Pathogenic:2

Robarts Research Institute, Western University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Cardiovascular phenotype

Pathogenic:1

May 12, 2017

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.653delG pathogenic mutation, located in coding exon 4 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 653, causing a translational frameshift with a predicted alternate stop codon (p.G218Vfs*47). This alteration has been reported in multiple hypercholesterolemia patients of various ethnic backgrounds (Giesel J et al. Hum. Genet., 1995 Sep;96:301-4; Wang J et al. Hum. Mutat., 2001 Oct;18:359; Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Day IN et al. Hum. Mutat., 1997;10:116-27). In addition to the clinical data reported in the literation, 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

4.2

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over