rs879254734

Variant names:

• chr19-11110640-G-A
• rs879254734
• NM_000527.5:c.941-12G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 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 intron
• Scores: Splicing: ADA: 0.6993
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7 U:1 B:1
• Conservation: PhyloP100: -1.79
• Publications: 2 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: Likely_pathogenic. The variant received 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.

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.941-12G>A		intron	N/A	NP_000518.1
	LDLR	NM_001195798.2		c.941-12G>A		intron	N/A	NP_001182727.1
	LDLR	NM_001195799.2		c.818-12G>A		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.941-12G>A		intron	N/A	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.1199-12G>A		intron	N/A	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.941-12G>A		intron	N/A	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Mar 30, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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).

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

Mar 01, 2016

Iberoamerican FH Network

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Jan 02, 2018

Robarts Research Institute, Western University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation;literature only

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subject mutated among 2600 FH index cases screened = 1

not provided Pathogenic:1

Mar 02, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Cardiovascular phenotype Pathogenic:1

Nov 15, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.941-12G>A intronic variant results from a G to A substitution 12 nucleotides upstream from coding exon 7 in the LDLR gene. This variant was identified in one or more individuals with features consistent with familial hypercholesterolemia (FH) and segregated with disease in at least one family (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Albuquerque J et al. Atherosclerosis, 2023 Oct;383:117314; Ambry internal data). In a RT-PCR assay, this variant showed a functionally abnormal splicing result (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.62
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=21/79	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879254734; hg19: chr19-11221316;