chr19-11110781-G-A

Variant names:

• chr19-11110781-G-A
• rs12710260
• NM_000527.5:c.1060+10G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_Moderate PP5

The NM_000527.5(LDLR):​c.1060+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:9
• Conservation: PhyloP100: -2.63
• Publications: 35 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 3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 19-11110781-G-A is Pathogenic according to our data. Variant chr19-11110781-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 251625.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1060+10G>A		intron_variant	Intron 7 of 17	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1060+10G>A		intron_variant	Intron 7 of 17	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249942 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460120 Hom.: 0 Cov.: 45 AF XY: 0.00000688 AC XY: 5 AN XY: 726478

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39670

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111790

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2 Uncertain:4

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 = 6 , family member = 1 -

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

- -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The c.1060+10G>A variant in LDLR has been reported in 6 individuals (including 3 French and 2 Italian individuals) with Familial Hypercholesterolemia, segregated with disease in 2 affected relatives from 1 family (PMID: 12436241, 23375686, 28965616), and has been identified in 0.01088% (2/18376) of East Asian chromosomes and 0.003267% (1/30608) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12710260). This variant has also been reported as a VUS, a likely benign variant, and a likely pathogenic variant in ClinVar (Variation ID: 251625). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the c.1060+10G>A variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting (Richards 2015). -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 02, 2018

Robarts Research Institute, Western University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Familial hypercholesterolemia Pathogenic:2 Uncertain:2

Jun 24, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to A nucleotide substitution at the +10 position of intron 7 of the LDLR gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, RNA studies have not been performed for this variant. This variant has been reported in several heterozygous individuals affected with familial hypercholesterolemia (PMID: 12436241, 15823288, 23375686, 28965616, 32633265, 34297352, 33807407, 36991406). Some of these individuals also carried additional pathogenic variants in the same gene (PMID: 32633265, 33807407). This variant has been identified in 3/249942 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

At least 7 reports of c.1060+10G>A in confirmed unrelated FH cases have been made (PMID: 12436241; 16542394; 23375686; 28965616; 36991406) allowing PS4_moderate to be scored. A further 3 three reports have also been published, but without a confirmed diagnosis (PMID: 15823288; 26332594; 34456049). PM2 and PP4 can also be scored, allowing a Uncertain significance classification to be made. -

Jun 20, 2025

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.1060+10G>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Three predict the variant strengthens a cryptic 5' donor site. One predicts the variant creates a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 249942 control chromosomes. c.1060+10G>A has been observed in multiple heterozygous and at least 1 homozygous individual(s) affected with autosomal dominant and autosomal recessive Familial Hypercholesterolemia (example, Marco_2022, Zhang_2023, Huang_2024, Labcorp Genetics (formerly Invitae)). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12436241, 23375686, 16542394, 34456049, 28965616, 36991406, 39731075, 15823288). ClinVar contains an entry for this variant (Variation ID: 251625). Based on the evidence outlined above, the variant was classified as pathogenic for autosomal dominant and autosomal recessive familial hypercholesterolemia. -

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 7 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. This variant is present in population databases (rs12710260, gnomAD 0.006%). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 12436241, 15823288, 23375686, 34297352, 34456049, 36991406; internal data). 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. ClinVar contains an entry for this variant (Variation ID: 251625). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:2

Feb 20, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in both heterozygous and homozygous states in several unrelated individuals with a clinical diagnosis of FH (PMID: 12436241, 23375686, 15823288, 34297352, 34456049, 28965616, 36991406); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 26332594, 15823288, 23375686, 28965616, 12436241, 34297352, 36991406, 34456049) -

Jan 09, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population, 0.000012 (3/249942 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with familial hypercholesterolemia (PMIDs: 28965616 (2017), 23375686 (2013), 15823288 (2005), 12436241 (2002)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on LDLR mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant. -

Cardiovascular phenotype Uncertain:1

Apr 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1060+10G>A intronic alteration consists of a G to A substitution 10 nucleotides after exon 7 of the LDLR gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	20
DANN	Benign	0.86
PhyloP100		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=27/70	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.93		Position offset: 1

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

Other links and lift over

dbSNP: rs12710260; hg19: chr19-11221457;