rs879254687

Variant names:

• chr19-11107390-A-G
• rs879254687
• NM_000527.5:c.818-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PP1_Moderate PS3_Supporting PM2 PVS1 PP4 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.818-2A>G variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PP1_Moderate, PM2, PP4, PS3_Supporting and PS4_Supporting) 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: PVS1 - variant is in +2 AG splice site and has been proven to result in retention of 10 nt of intron5, which lead to out of frame consequence: p.Val273Glufs*31, so PVS1 is met.PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis from 2 families from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge - 3 relatives with the phenotype have the variant and 2 relatives without phenotype do not have the variant. PP1_Moderate is met.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP4 - variant meets PM2. Identified in 3 unrelated index cases who fulfill SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. PP4 is metPS3_supporting - Level 3 FS: Medeiros et al., 2010 (PMID 20828696) - Htz patients' lymphocytes, RNA assays - results: Retention of 10 nt of intron5 (p.Val273Glufs*31) --- an aberrant transcript was identified, so PS3_Supporting is metPS4_supporting - variant meets PM2. Identified in 3 unrelated index cases who fulfill SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. PS4_Supporting is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585149/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 7.35
• Publications: 5 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: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for LDLR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.818-2A>G		splice_acceptor intron	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.818-2A>G		splice_acceptor intron	N/A	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.695-2A>G		splice_acceptor intron	N/A	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.818-2A>G		splice_acceptor intron	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1076-2A>G		splice_acceptor intron	N/A	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.818-2A>G		splice_acceptor intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Hypercholesterolemia, familial, 1 (4)
2	-	-	Familial hypercholesterolemia (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	LDLR-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		7.4
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.64		Position offset: 16
DS_AL_spliceai		0.99		Position offset: 2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs879254687;

hg19: chr19-11218066;