rs879254734

Positions:

• chr19-11110640-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS3_Supporting PM2 PP4 PP1 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR): c.941-12G>A variant is classified as Likely Pathogenic evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4_Supporting, PP1) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 Met: This variant is absent in gnomAD (gnomAD v2.1.1).PP4 Met: This variant meets PM2 and is identified in >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded.PS4_Supporting Met: Variant meets PM2, and is identified in 4 unrelated index cases who fulfil DLCN criteria for FH diagnosis from 2 different labs: Three cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); one case from Robarts Research Institute, Canada. PP1 Met: Variant segregates with FH phenotype in 3 informative meiosis in one family (Institut National de la Santé et de la Recherche Médicale,and Université Paris Descartes, Paris, France, PMID:20809525).PS3_Supporting: RNA assay using patient monocytes (level 3 functional assay) was reported from one research lab. Abnormal splicing of intron 6 was observed by gel electrophoresis only in patient cDNA but not in controls, using forward primer with 5' end located at c.864 (exon 6) and the reverse primer with 3' end at c.941-11. Sequencing confirmation on abnormal RT-PCR product was not performed and aberrant transcript was not quantified (Institut National de la Santé et de la Recherche Médicale,and Université Paris Descartes, Paris, France, PMID:20809525). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585217/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.6993
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:1 B:1
• Conservation: PhyloP100: -1.79

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 6 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.941-12G>A		splice_polypyrimidine_tract_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.941-12G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:5 Uncertain:1 Benign:1

Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 30, 2022	The NM_000527.5 (LDLR): c.941-12G>A variant is classified as Likely Pathogenic evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4_Supporting, PP1) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 Met: This variant is absent in gnomAD (gnomAD v2.1.1). PP4 Met: This variant meets PM2 and is identified in >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4_Supporting Met: Variant meets PM2, and is identified in 4 unrelated index cases who fulfil DLCN criteria for FH diagnosis from 2 different labs: Three cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); one case from Robarts Research Institute, Canada. PP1 Met: Variant segregates with FH phenotype in 3 informative meiosis in one family (Institut National de la Santé et de la Recherche Médicale,and Université Paris Descartes, Paris, France, PMID: 20809525). PS3_Supporting: RNA assay using patient monocytes (level 3 functional assay) was reported from one research lab. Abnormal splicing of intron 6 was observed by gel electrophoresis only in patient cDNA but not in controls, using forward primer with 5' end located at c.864 (exon 6) and the reverse primer with 3' end at c.941-11. Sequencing confirmation on abnormal RT-PCR product was not performed and aberrant transcript was not quantified (Institut National de la Santé et de la Recherche Médicale,and Université Paris Descartes, Paris, France, PMID: 20809525). -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -
Likely pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
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	subject mutated among 2600 FH index cases screened = 1 -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 02, 2023

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect with abnormal splicing of intron 6 observed by gel electrophoresis (Marduel et al., 2010); This variant is associated with the following publications: (PMID: 20809525) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.70
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 2
DS_AL_spliceai		0.53		Position offset: 12

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

Publications

LitVar

Other links and lift over

dbSNP: rs879254734; hg19: chr19-11221316;