Variant chr19-11105218-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_000527.5(LDLR):c.314-2A>C variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000657 in 152,150 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

LDLR
NM_000527.5 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

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

Conservation

PhyloP100: 4.63

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.14711575 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-11105218-A-C is Pathogenic according to our data. Variant chr19-11105218-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105218-A-C 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.314-2A>C		splice_acceptor_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.314-2A>C		splice_acceptor_variant		1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

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:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 08, 2022	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -

Familial hypercholesterolemia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 18, 2023	The c.314-2A>C intronic variant, also known as IVS3-2A>C is located at the canonical acceptor splice site of intron 3 of the LDLR gene, that encodes for low density lipoprotein receptor. This variant has been reported in at least ten individuals affected with familial hypercholesterolemia (FH) (PMID:11668627, 27765764, 34037665, 32220565). Another intronic variant affecting the same nucleotide, c.314-2A>G, has also been reported in individuals with FH (PMID: 27824480). Variants affecting the same splice site (c.314-1G>A and c.314-3C>T) have been observed in individuals diagnosed with FH (PMID 11810272, 16250003). In-silico computational prediction tools suggest that the c.314-2A>C variant likely leads to acceptor loss (SpliceAI: 0.99 [acceptor loss], 0.32 [acceptor gain at +10bp position]) and disturb normal splicing, resulting in aberrant or absence of protein product (PMID: 16199547). This variant is absent in the general population database, gnomAD. This variant has been interpreted as likely pathogenic/pathogenic by multiple submitters in the ClinVar database (ID: 251142). Therefore, the c.314-2A>C intronic variant in the LDLR gene is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 05, 2023	This variant (also known as IVS3-2A>C) causes an A to C nucleotide substitution at the -2 canonical splice acceptor site of intron 3 of the LDLR gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in at least 8 individuals affected with familial hypercholesterolemia (PMID: 11668627, 27765764, 27824480, 32220565). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease. Based on available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change affects an acceptor splice site in intron 3 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 27765764, 27824480). This variant is also known as IVS3-2A>C inthe literature. ClinVar contains an entry for this variant (Variation ID: 251142). 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. -

Homozygous familial hypercholesterolemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 21, 2018

The c.314-2A>C variant in LDLR has been reported in the heterozygous state in at least 5 individuals with familial hypercholesterolemia (FH; Wang 2001, Wang 2016. This variant has also been reported in ClinVar (Variation ID: 251142) and was absent from 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 the activation of a downstream splice site that would result in the first 8 bases of the exon to be spliced out, causing a frameshift which alters the protein's amino acid sequence and leads to a premature termination codon 22 amino acids downstream. In summary, although additional studies are required to fully establish its clinical significance, the c.314-2A>C variant is likely pathogenic. ACMG/AMP Criteria applied (Richards 2015): PVS1_Strong; PM2; PS4_Supporting. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2023

Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 27765764, 31447099, 32041611, 26582918, 32220565, 33303402, 11668627, 34037665) -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2022

The c.314-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 4 in the LDLR gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration has been described in familial hypercholesterolemia (FH) cohorts (Wang J et al. Hum Mutat. 2001;18:359; Wang J et al. Arterioscler Thromb Vasc Biol, 2016 12;36:2439-2445; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Another alteration impacting the same acceptor site (c.314-1G>A) has also been detected in individuals with FH (Huijgen et al 2010; Hum Mut 31(6):752-60; Lombardi P et al. Hum Mutat, 1998;Suppl 1:S172-4; Luirink IK et al. Atherosclerosis, 2019 06;285:87-92). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

1.0

MutationTaster

Benign

1.0

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

GERP RS

5.3

RBP_binding_hub_radar

0.67

RBP_regulation_power_radar

2.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.81

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.32

Position offset: 10

DS_AL_spliceai

0.99

Position offset: 2

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

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