Variant rs875989926 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000558518.6(LDLR):c.1705+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LDLR
ENST00000558518.6 splice_donor

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 9.87

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.1, offset of -40, new splice context is: ctgGTgact. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-11116213-G-A is Pathogenic according to our data. Variant chr19-11116213-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11116213-G-A is described in Lovd as [Pathogenic]. Variant chr19-11116213-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.1705+1G>A		splice_donor_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.1705+1G>A		splice_donor_variant		1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1443884

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719598

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.13e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:5

Pathogenic, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Mar 27, 2018	The c.1705+1G>A variant in the LDLR gene disrupts the canonical splice donor site in intron 11 and is predicted to result in abnormal mRNA splicing. This variant has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 10532689, 19318025, 20145306). The c.1705+1G>A variant in the LDLR gene is classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jun 01, 2011	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -

Homozygous familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 11, 2018

The c.1705+1G>A variant in LDLR has been reported in 6 Caucasian individuals wit h hypercholesterolemia (Jensen 1999, Chmara 2010, Sharifi 2016) and was absent f rom large population studies. This variant occurs in the invariant region (+/- 1 ,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Furthermore, other variants in the sam e splice consensus sequence have been reported in individuals with hypercholeste rolemia (c.1705+1G>C, c.1705+1G>T). In vitro functional studies of the c.1705+1G >T and the c.1705+1G>A variants provide some evidence of abnormal splicing (R?dn ingen 1999; Holla 2009). In summary, this variant meets criteria to be classifie d as pathogenic for hypercholesterolemia in an autosomal dominant manner based u pon proband counts, absence from controls, and functional impact. ACMG/AMP Crite ria applied: PVS1; PM2; PS4_Supporting; PS3_Supporting. -

LDLR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 15, 2022

The LDLR c.1705+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported as pathogenic for autosomal dominant familial hypercholesterolemia (Jensen et al 1999. PubMed ID: 10532689; Table S1, Leren et al 2021. PubMed ID: 33740630; eTable 1, Sturm et al 2021. PubMed ID: 34037665; Chmara et al 2010. PubMed ID: 20145306; Sharifi et al 2015. PubMed ID: 26892515). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2019

The c.1705+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 11 of the LDLR gene. This alteration has been detected in several individuals with familial hypercholesterolemia (FH) (Jensen HK et al. Atherosclerosis, 1999 Oct;146:337-44; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 23, 2019

For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). Experimental studies have shown that this chance results in exon skipping and in reduced LDLR activity (PMID: 19208450). This variant was observed in individuals affected with familial hypercholesterolemia (PMID: 10532689, 20145306, 19208450, 17406740). ¬† ClinVar contains an entry for this variant (Variation ID: 226367). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 11 of the LDLR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Benign

0.95

Eigen

Pathogenic

0.80

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.84

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.54

Position offset: -41

DS_DL_spliceai

1.0

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.

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