rs139617694

Variant names:

• chr19-11113534-G-A
• rs139617694
• NM_000527.5:c.1359-1G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11113534-G-A
• chr19-11113534-G-C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS4 PP1_Strong PS3_Supporting PVS1 PM2 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1359-1G>A variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PP1_Strong, PS4, PM2, PP4 and PS3_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 canonical - 1 splice site and causes a frameshift in exon 10 (p.Thr454Leufs*51, from Holla et al., 2009 (PMID 19208450)), so PVS1 is met.PP1_strong - variant segregates with FH phenotype in 9 informative meiosis from at least 5 families:- 5 informative meiosis from 4 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): 5 relatives with the variant have LDL-C >75th percentile.- 4 informative meiosis from at least 1 family from Mayo lab (Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), Ambry lab (Ambry Genetics) and Arca lab (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca), but are confirmed to be the same: 2 relatives with the variant had LDL >75th percentile and 2 relatives negative for variant had LDL <50th percentile.--- so PP1_Strong is met.PS4 - variant meets PM2 and was identified in:- 25 unrelated index cases (22 cases with DLCN >=6, 3 with possible Simon Broome FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France;- 2 unrelated index cases (MFH101: DLCN of 8, MFH116: meets MEDPED definite) reported by Mayo lab (Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), Ambry lab (Ambry Genetics) and Arca lab (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca), but are confirmed to be the same;- 1 index case with Dutch lipid clinic network >=6 from Robarts Research Institute, Canada;- 1 index case with DLCN >= 6 from Color Health, Inc., USA.--- 29 cases (no additional bibliographic search was done because number of index cases is already over 10), so PS4 is met.PM2 - PopMax MAF = 0.00002940 (0.003%) in European non-Finnish genomes (gnomAD v3.1.2). It is below 0.02%, so PM2 is met.PP4 - variant meets PM2 and was identified in at least 29 unrelated index cases (see PS4 for details), so PP4 is met.PS3_supporting - Level 2/3 FS: Holla et al., 2009 (PMID 19208450): Htz patients' Epstein Barr virus transformed lymphocytes, RNA assays - results: skipping of the first 7 nts from exon 10 in 23% of mRNAs (p.Thr454Leufs*51)--- aberrant transcript is confirmed by sequencing and is quantified, but it is not above 25% of total transcript, so PS3_Supporting is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023463/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: LDLR NM_000527.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:26
• Conservation: PhyloP100: 6.43
• Publications: 8 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]

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Pathogenic. The variant received 20 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.1359-1G>A		splice_acceptor intron	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1359-1G>A		splice_acceptor intron	N/A	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1236-1G>A		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.1359-1G>A		splice_acceptor intron	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1617-1G>A		splice_acceptor intron	N/A	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1359-1G>A		splice_acceptor intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152124 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 250786 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461550 Hom.: 0 Cov.: 38 AF XY: 0.00000963 AC XY: 7 AN XY: 727074

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111930

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152124 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000950 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
15	-	-	Hypercholesterolemia, familial, 1 (15)
5	-	-	not provided (5)
2	-	-	Familial hypercholesterolemia (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Homozygous familial hypercholesterolemia (1)
1	-	-	Hypercholesterolemia (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.4
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: 8
DS_AL_spliceai		1.0		Position offset: 1

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

Other links and lift over

dbSNP: rs139617694; hg19: chr19-11224210;