rs879254467

chr19-11102791-G-Achr19-11102791-G-Cchr19-11102791-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000527.5(LDLR):c.313+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3
• Conservation: PhyloP100: 9.39

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 19-11102791-G-A is Pathogenic according to our data. Variant chr19-11102791-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 251136.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=3, Pathogenic=1}. Variant chr19-11102791-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.313+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.313+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2 Uncertain:2

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
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 = 4/FH-Europe -
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	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 27, 2023

Reported in individuals with FH, either in the compound heterozygous state or state not reported (PMID: 30592178, 11317362); Not observed at significant frequency in large population cohorts (gnomAD); Functional studies demonstrate exon 3 skipping (PMID: 11317362); Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; A different change at this position, c.313+5 G>T, has been reported patients with FH (PMID: 16806138; HGMD); This variant is associated with the following publications: (PMID: 25525159, 11317362, 17094996, 30592178, 31102204, 16806138) -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 05, 2023

The c.313+5G>A intronic alteration consists of a G to A substitution nucleotides after coding exon 3 in the LDLR gene. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in several individuals with familial hypercholesterolemia (FH) (Tosi, 2007; Chan, 2019; Liguori, 2001; Ambry internal data). Another alteration impacting the same donor site (c.313+6T>C) has been shown to have a similar impact on splicing and has also been reported in association with FH (Bourbon, 2009; Rieck, 2020). This nucleotide position is highly conserved in available vertebrate species. In one study, authors used RT-PCR to show that this alteration induces abnormal splicing resulting in an in-frame deletion of 41 amino acids (coding exon 3 skipping) in the ligand binding domain (Liguori, 2001) In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as likely pathogenic. -

Familial hypercholesterolemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 12, 2023

This sequence change falls in intron 3 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 11317362, 17094996, 30592178; Invitae). ClinVar contains an entry for this variant (Variation ID: 251136). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
Cadd	Benign	19
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.70		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs879254467; hg19: chr19-11213467;