chr19-11116213-G-A

Variant names:

• chr19-11116213-G-A
• rs875989926
• NM_000527.5:c.1705+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000527.5(LDLR):​c.1705+1G>A variant causes a splice donor, intron 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 NM_000527.5 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.87
• Publications: 5 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 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 226367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1705+1G>A		splice_donor intron	N/A	NP_000518.1
	LDLR	NM_001195798.2		c.1705+1G>A		splice_donor intron	N/A	NP_001182727.1
	LDLR	NM_001195799.2		c.1582+1G>A		splice_donor intron	N/A	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1705+1G>A		splice_donor intron	N/A	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.1963+1G>A		splice_donor intron	N/A	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1705+1G>A		splice_donor intron	N/A	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443884 Hom.: 0 Cov.: 26 AF XY: 0.00000139 AC XY: 1 AN XY: 719598

African (AFR) AF: 0.00 AC: 0 AN: 33054

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 85910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095802

Other (OTH) AF: 0.00 AC: 0 AN: 59768

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:5

Mar 27, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

Jun 01, 2011

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

Iberoamerican FH Network

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation;literature only

Homozygous familial hypercholesterolemia Pathogenic:1

Jun 11, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 15, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 16, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. 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

Feb 23, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency). 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). Experimental studies have shown that this chance results in exon skipping and in reduced LDLR activity (PMID: 19208450). 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). 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	34
DANN	Benign	0.95
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		9.9
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs875989926; hg19: chr19-11226889;