Variant 19-11110781-G-A details in Genebe, Genetics Data Aggregator

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:

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.1060+10G>A		intron_variant		ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1060+10G>A		intron_variant		1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249942

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135342

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1460120

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726478

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:2Uncertain:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subjects mutated among 2600 FH index cases screened = 6 , family member = 1 -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	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). -
Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 09, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2024	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) -

Familial hypercholesterolemia

Uncertain:2

Uncertain significance, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 09, 2022	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 individual(s) with hypercholesterolemia (PMID: 12436241, 15823288, 23375686). 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 create or strengthen a splice site. 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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 10, 2024

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 3' acceptor 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 (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1060+10G>A has been reported in the literature in individuals affected with Hypercholesterolemia (examples: Brusgaard_2006, Amsellem_2011, Bertolini_2013, Pirillo_2017, Marco-Bened_2022, Zhang_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. The following publications have been ascertained in the context of this evaluation (PMID: 34456049, 12436241, 23375686, 16542394, 28965616, 36991406). ClinVar contains an entry for this variant (Variation ID: 251625). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2023

The c.1060+10G>A intronic variant results from a G to A substitution 10 nucleotides after coding exon 7 in the LDLR gene. This alteration has been reported in the heterozygous and homozygous states in multiple patients with features of familial hypercholesterolemia (Amsellem S et al. Hum Genet, 2002 Dec;111:501-10; Damgaard D et al. Atherosclerosis, 2005 May;180:155-60; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Pirillo A et al. Atheroscler Suppl, 2017 Oct;29:17-24; Marco-Benedí V et al. Atherosclerosis, 2022 May;349:211-218). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. 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

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.86

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

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

Publications

LitVar

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

19-11110781-G-A

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