rs879254823

Positions:

• chr19-11113276-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000527.5(LDLR):​c.1187-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. 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: 29)
• Consequence: LDLR NM_000527.5 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.63

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11113276-A-G is Pathogenic according to our data. Variant chr19-11113276-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113276-A-G is described in Lovd as [Pathogenic]. Variant chr19-11113276-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1187-2A>G		splice_acceptor_variant, intron_variant		ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1187-2A>G		splice_acceptor_variant, intron_variant		1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 14, 2023	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PVS1+PS4_Supporting+PP1 -
Pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2017	The c.1187-2 A>G variant has been reported in the heterozygous state in one Norwegian proband with FH (Holla et al., 2009). This variant destroys the canonical splice acceptor site located at the intron 8/exon 9 junction, and is predicted to cause abnormal gene splicing. This variant is predicted to lead to an abnormal message that is subject to nonsense-mediated mRNA decay, consistent with comprehensive mRNA splicing studies determined by wet-lab analyses in the same study by Holla et al. (2009). In addition, other downstream splice site variants in the LDLR gene have been reported in HGMD in association with FH (Stenson et al., 2014), indicating that loss of function is a known disease mechanism. Furthermore, the c.1187-2 A>G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, c.1187-2 A>G in the LDLR gene is interpreted as a pathogenic variant. -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 12, 2022

Studies have shown that disruption of this splice site alters LDLR gene expression (PMID: 19208450). This sequence change affects an acceptor splice site in intron 8 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 individual(s) with familial hypercholesterolemia (PMID: 19208450). ClinVar contains an entry for this variant (Variation ID: 251713). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.59		Position offset: 45
DS_AL_spliceai		1.0		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs879254823; hg19: chr19-11223952;