chr19-11128087-T-G

Variant names:

• chr19-11128087-T-G
• rs879255188
• NM_000527.5:c.2389+2T>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Strong PP1_Moderate PM2 PP4 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.2389+2T>G variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1_Strong, PP1_moderate, PM2, PP4 and PS4_Supporting, as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1_strong - variant is at +2 donor splice site, and is predicted to lead to exon 16 skipping. Exon 16 is in frame, so PVS1_Strong is met.PP1_moderate - variant segregates with FH phenotype in 5 relatives from Robarts Research Institute, so PP1_Moderate is met.PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met.PS4_Supporting - variant meets PM2 and is identified in 3 unrelated index cases, after alternative causes of hypercholesterolemia were excluded, from different labs (1 with DLCN >=6 from Robarts Research Institute, 1 with possible FH according to Simon-Broome criteria from PMID 17539906 (UK) and 1 with DLCN >=6 from PMID 33418990 (Russia)), so PS4_Supporting is met.PP4 - variant meets PM2 and is identified in 3 unrelated index cases from different labs (see PS4 for details), so PP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585839/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 3.91
• Publications: 1 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: 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.2389+2T>G		splice_donor intron	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.2389+2T>G		splice_donor intron	N/A	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.2266+2T>G		splice_donor 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.2389+2T>G		splice_donor intron	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.2647+2T>G		splice_donor intron	N/A	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.2389+2T>G		splice_donor intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Hypercholesterolemia, familial, 1 (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	0.98
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		3.9
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: 31
DS_DL_spliceai		0.99		Position offset: -2

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

Other links and lift over

dbSNP: rs879255188; hg19: chr19-11238763;