rs875989944

Variant names:

• chr19-11129515-CTCCTCGTCT-C
• rs875989944
• NM_000527.5:c.2397_2405delCGTCTTCCT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM4 PP5

The NM_000527.5(LDLR):​c.2397_2405delCGTCTTCCT​(p.Val800_Leu802del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,534 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L799L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: LDLR NM_000527.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:17 U:7
• Conservation: PhyloP100: 7.51
• Publications: 2 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 15 uncertain in NM_000527.5
• PM4: Nonframeshift variant in NON repetitive region in NM_000527.5.
• PP5: Variant 19-11129515-CTCCTCGTCT-C is Pathogenic according to our data. Variant chr19-11129515-CTCCTCGTCT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 226394.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2397_2405delCGTCTTCCT	p.Val800_Leu802del	disruptive_inframe_deletion	Exon 17 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2397_2405delCGTCTTCCT	p.Val800_Leu802del	disruptive_inframe_deletion	Exon 17 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152142 Hom.: 0 Cov.: 31

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251148 AF XY: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461392 Hom.: 0 AF XY: 0.0000165 AC XY: 12 AN XY: 727052

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152142 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74306

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:17 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:13 Uncertain:2

Mar 01, 2016

Iberoamerican FH Network

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 25, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an in-frame deletion of three amino acids from the transmembrane domain of the LDLR protein. This variant has been reported to occur in cis with p.Asn564His (c.1690A>C) variant located in the LDLR type B repeat 4 of the EGF precursor homology domain domain of the LDLR protein in numerous individuals affected with familial hypercholesterolemia (PMID: 9143924, 9143924, 10090484, 12442279, 12442279, 15241806, 21475731, 24632281, 27784735, 27919364, 28475941, 30795984, 32143996, 34387892). The double mutant allele is common among affected individuals of Spanish descent (PMID: 2463228) and is thought to be a founder mutation associated with mild phenotype in the Dutch population (PMID: 21475731). The double mutant allele has been shown to segregate with disease in multiple families (PMID: 9143924, 12442279). This p.Val800_Leu802 variant has been identified in 2/251416 chromosomes in the general population by the Genome Aggregation Database (gnomAD), and it is unknown if these two alleles carry p.Asn564His (c.1690A>C) variant in cis. In one functional study, a mutant protein carrying either p.Asn564His or p.Val800_Leu802 variant showed wild type-like LDLR cell surface expression and function in transfected cells, while a mutant protein carrying both variants resulted in significantly reduced LDLR cell surface expression and function (20-30% of the wild type activity as measured by flow cytometry) (PMID: 9143924). It remains a possibility that the two variants may act in synergy to adversely affect LDLR function (PMID: 9143924). However, different missense variants that alter asparagine at codon 564 (p.Asn564Ser and p.Asn564Asp) are reported as disease-causing, indicating the functional and clinical importance of p.Asn564 residue (ClinVar variation ID: 224616, 251973). Based on the available evidence, we conclude that the hypercholesterolemia phenotype observed in individuals carrying the double mutant allele may be attributable to p.Asn564His variant, while the role of p.Val800_Leu802 variant in disease remains unclear. Therefore, this p.Val800_Leu802 variant is classified as a Variant of Uncertain Significance. -

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 17, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4,PP1_STR,PM2,PS3_SUP,PP3 -

-

Robarts Research Institute, Western University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subjects mutated among 2600 FH index cases screened = 8 , family member = 1 with co-segregation / systematically associated with c.1690A>C, p.Asn564His -

Aug 01, 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

Fundacion Hipercolesterolemia Familiar

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 04, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 02, 2018

Robarts Research Institute, Western University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 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

- -

Jun 13, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:4 Uncertain:1

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 11, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Functional studies suggest p.(N564H) in cis with LDLR p.(V800_L802del) (also reported as p.(S820_N22del) due to alternate nomenclature) results in an affect on the enzyme function (PMID: 9143924, 12442279); In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22390909, 30795984, 31447099, 9147888, 9143924, 12442279, 33740630, 32770674, 34456049, 32719484) -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDLR: PM2, PM4, PS4:Moderate, PS3:Supporting -

Jan 31, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PM2_moderate, PS3_moderate, PS4 -

Familial hypercholesterolemia Uncertain:2

Mar 24, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an in-frame deletion of three amino acids from the transmembrane domain of the LDLR protein. This variant has been reported to occur in cis with p.Asn564His (c.1690A>C) variant located in the LDLR type B repeat 4 of the EGF precursor homology domain domain of the LDLR protein in numerous individuals affected with familial hypercholesterolemia (PMID: 9143924, 9143924, 10090484, 12442279, 12442279, 15241806, 21475731, 24632281, 27784735, 27919364, 28475941, 30795984, 32143996, 34387892, 34456049, 38523000). The double mutant allele is common among affected individuals of Spanish descent (PMID: 2463228) and is thought to be a founder mutation associated with mild phenotype in the Dutch population (PMID: 21475731). The double mutant allele has been shown to segregate with disease in multiple families (PMID: 9143924, 12442279). This p.Val800_Leu802 variant has been identified in 2/251416 chromosomes in the general population by the Genome Aggregation Database (gnomAD), and it is unknown if these two alleles carry p.Asn564His (c.1690A>C) variant in cis. In one functional study, a mutant protein carrying either p.Asn564His or p.Val800_Leu802 variant showed wild type-like LDLR cell surface expression and function in transfected cells, while a mutant protein carrying both variants resulted in significantly reduced LDLR cell surface expression and function (20-30% of the wild type activity as measured by flow cytometry) (PMID: 9143924). It remains a possibility that the two variants may act in synergy to adversely affect LDLR function (PMID: 9143924). However, different missense variants that alter asparagine at codon 564 (p.Asn564Ser and p.Asn564Asp) are reported as disease-causing, indicating the functional and clinical importance of p.Asn564 residue (ClinVar variation ID: 224616, 251973). Based on the available evidence, we conclude that the hypercholesterolemia phenotype observed in individuals carrying the double mutant allele may be attributable to p.Asn564His variant, while the role of p.Val800_Leu802 variant in disease remains unclear. Therefore, this p.Val800_Leu802 variant is classified as a Variant of Uncertain Significance. -

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.2397_2405del, results in the deletion of 3 amino acid(s) of the LDLR protein (p.Val800_Leu802del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has been observed in individual(s) with familial hypercholesterolemia. This variant is frequently in cis with p.Asn564His and may represent a single allele (PMID: 9143924, 9147888, 10090484, 12442279, 30795984). This variant is also known as 2393del9. ClinVar contains an entry for this variant (Variation ID: 226394). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 9143924). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Jul 28, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.2397_2405delCGTCTTCCT (p.Val800_Leu802del) results in an in-frame deletion that is predicted to remove 3 amino acids from the encoded protein. The variant allele was found at a frequency of 8e-06 in 251148 control chromosomes (i.e. 2 alleles in the European (non-Finnish) subpopulation) in the gnomAD database (v2.1 dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.2397_2405delCGTCTTCCT (aka. 2393del9), has been reported in the literature in several individuals affected with Familial Hypercholesterolemia (e.g. Jensen_1996, Castillo_2002, Fouchier_2001, Umans-Eckenhausen_2002, Kusters_2011, Sjouke_2016, Martin-Campos_2018, Leren_2021), however in almost all of these cases the variant reportedly occurred together with c.1690A>C (p.Asn564His) on the same chromosome (i.e. in cis), as a complex allele. These reports therefore do not provide unequivocal conclusions about association of the variant in isolation with Familial Hypercholesterolemia. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that when this variant was expressed in isolation, it had a mild effect on LDLR function (~75-85% activity of the normal; Jensen_1996), however, when it was part of the complex allele, i.e. occurring together with p.Asn564His in the same protein, the LDLR receptor function was markedly reduced (to ~20-25% of the normal; Jensen_1996, Castillo_2002). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=1), likely pathogenic (n=4), or pathogenic (n=4). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype Uncertain:1

Jul 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2397_2405delCGTCTTCCT variant (also known as p.V800_L802del) is located in coding exon 17 of the LDLR gene. This variant results from an in-frame CGTCTTCCT deletion at nucleotide positions 2397 to 2405. This results in the in-frame deletion of the amino acids at codon 800 to 802. This alteration has been reported in familial hypercholesterolemia (FH) cohorts and is often described on the same chromosome, or in cis, with the alteration, p.N564H (Alonso R et al. J Clin Lipidol Apr;10:953-961; Lombardi P et al. Clin Genet, 1996 Dec;50:525-6; Jensen HK et al. Atherosclerosis, 1999 Oct;146:337-44; Ebhardt M et al. Hum Mutat, 1999;13:257; Fouchier SW et al. Hum Genet, 2001 Dec;109:602-15; Mozas P et al. Hum Mutat, 2004 Aug;24:187; Martín-Campos JM et al. J Clin Lipidol Sep;12:1452-1462). This amino acid position ranges from not well to poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs875989944; hg19: chr19-11240191;