19-11123248-C-T

Variant names:

• chr19-11123248-C-T
• rs370018159
• NM_000527.5:c.2215C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PVS1 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR) :c.2215C>T (p.Gln739Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence code PVS1, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PVS1 - Stop in codon 739. It is upstream of amino acid 830.PP4 - Variant meets PM2 and is identified in one index case who fulfill FH/DLCN>=6 criteria for FH from Robarts Research Institute after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585809/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 30)
• Consequence: LDLR NM_000527.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:13 U:1
• Conservation: PhyloP100: -0.203
• Publications: 12 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2215C>T	p.Gln739*	stop_gained	Exon 15 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2215C>T	p.Gln739*	stop_gained	Exon 15 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:5 Uncertain:1

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subject mutated among 2600 FH index cases screened = 1/FH-Japan -

Jun 04, 2019

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

Significance: 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

- -

May 24, 2021

Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Robarts Research Institute, Western University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 29, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR) :c.2215C>T (p.Gln739Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence code PVS1, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PVS1 - Stop in codon 739. It is upstream of amino acid 830. PP4 - Variant meets PM2 and is identified in one index case who fulfill FH/DLCN>=6 criteria for FH from Robarts Research Institute after alternative causes of high cholesterol were excluded. -

Familial hypercholesterolemia Pathogenic:5

Mar 25, 2025

GENinCode PLC

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.2215C>T p.(Gln739Ter) variant is a nonsense variant predicted to result in a stop codon at amino acid 739, which is amino-terminal of amino acid 830 (PVS1_VERY STRONG). This variant has been reported in FH patients meeting clinical criteria, including patients where secondary causes of high cholesterol have been excluded (PS4_MODERATE, PP4_SUPPORTING; PMIDs 16314194, 20538126, 27765764, 28965616, 32220565, 32331935, 32423031, ClinGen FH VCEP data). This variant is absent from gnomAD v2.1.1 (PM2_MODERATE). Based on the evidence listed above, we have classified this variant as Pathogenic. -

Jun 18, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 29, 2019

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.2215C>T (p.Gln739X) 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 was absent in 251316 control chromosomes (gnomAD). c.2215C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Yu_2002, Robles-Osorio_2006, Romano_2010, Chiou_2010, Pirillo_2017, Kolansky_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reported that the variant resulted in less than 2% of normal LDLR activity in patient derived skin fibroblasts (Kolansky_2008). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and as VUS (1x). Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 03, 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.Gln739*) 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 individuals with familial hypercholesterolemia (PMID: 12417285, 20045108, 20538126, 21376320, 23375686). 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 p.Gln718X. ClinVar contains an entry for this variant (Variation ID: 252258). For these reasons, this variant has been classified as Pathogenic. -

Dec 14, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant (also known as Q718X) changes 1 nucleotide in exon 15 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID:12417285, 20045108, 20538126, 21376320, 23375686). 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. Based on available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:2

Jul 05, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Also known as p.(Q718*); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense 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; This variant is associated with the following publications: (PMID: 25525159, 32041611, 32331935, 32220565, 19026292, 28965616, 31491741, 33303402, 32423031, 23375686, 21376320, 20538126, 34037665, 20045108, 16314194, 12417285) -

Jul 23, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.2215C>T (p.Gln739*) variant causes the premature termination of LDLR protein synthesis. This variant has been reported in the published literature in multiple individuals with Familial Hypercholesterolemia (PMIDs: 12417285 (2002), 20538126 (2010), 21376320 (2011), 23375686 (2013), 28965616 (2017), 31491741 (2019), 32041611 (2020), 32331935 (2020), 32220565 (2020), 32423031(2020), 33303402 (2021), 33994402 (2021), 34297352 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

May 12, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q739* pathogenic mutation (also known as c.2215C>T), located in coding exon 15 of the LDLR gene, results from a C to T substitution at nucleotide position 2215. This changes the amino acid from a glutamine to a stop codon within coding exon 15. This variant was reported in individual(s) with features consistent with familial hypercholesterolemia (FH) (Yu W et al. Atherosclerosis, 2002 Dec;165:335-42; Robles-Osorio L et al. Arch Med Res, 2006 Jan;37:102-8; Kolansky DM et al. Am J Cardiol, 2008 Dec;102:1438-43; Chiou KR et al. Am J Cardiol, 2010 Jun;105:1752-8; Romano M et al. Atherosclerosis, 2010 Jun;210:493-6; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Wang J et al. Arterioscler Thromb Vasc Biol, 2016 12;36:2439-2445; Tada H et al. J Clin Lipidol 2020 Mar;14:346-351.e9; Di Taranto MD et al. Clin Genet, 2021 Nov;100:529-541; Gill PK et al. J Clin Lipidol 2021 Nov;15:79-87). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, 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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	34
DANN	Benign	0.92
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.088	N
PhyloP100		-0.20
Vest4		0.79
GERP RS		0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs370018159; hg19: chr19-11233924;