rs765696008

Variant names:

• chr19-11113268-G-A
• rs765696008
• NM_000527.5:c.1187-10G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11113268-G-A
• chr19-11113268-G-T
• chr19-11113268-G-C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PP3_Moderate PP5_Very_Strong

The NM_000527.5(LDLR):​c.1187-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,611,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002521688: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:26077743, 21865347)" and additional evidence is available in ClinVar. The gene LDLR is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: LDLR NM_000527.5 intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24
• Conservation: PhyloP100: -0.371
• Publications: 15 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

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

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002521688: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26077743, 21865347); SCV005418449: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.; SCV000544644: Experimental studies have shown that this variant affects LDLR function (PMID: 21865347).; SCV000697187: At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant affects RNA splicing. PMID: 11668627, 12436241, 16205024, 21865347, 26077743; SCV007100117: "In addition, functional studies in EBV-transformed lymphocytes demonstrated reduced LDLR activity (PS3_MODERATE; PMIDs 19208450 and 21865347)."; SCV002046469: "In addition, cell-based functional studies report this variant is damaging to LDLR protein activity by activating a cryptic splice acceptor site which leads to early termination of LDLR mRNA translation (PMIDs: 19208450 (2009), 21865347(2011), and 26077743 (2015))."; SCV005079221: Functional characterization in EBV-transformed lymphocytes showed a significant reduction in LDLR activity (PMID: 21865347, 19208450); SCV002634909: In vitro studies of patient-derived lymphocytes with this variant demonstrated reduced LDLR activity, and aberrant splicing has also been reported (Romano M et al, J. Lipid Res. 2011;52(11):2095-100; Sun LY et al, Sci Rep 2015;5:11380).; SCV004847647: "In vitro functional studies support an impact on protein function (Holla 2009, Romano 2011)."
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 19-11113268-G-A is Pathogenic according to our data. Variant chr19-11113268-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 226349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1187-10G>A		intron	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1187-10G>A		intron	N/A	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1064-10G>A		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.1187-10G>A		intron	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1445-10G>A		intron	N/A	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1187-10G>A		intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151920 Hom.: 0 Cov.: 29

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: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000280 AC: 7 AN: 250138 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1459908 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 726254

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86180

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4656

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111888

Other (OTH) AF: 0.0000498 AC: 3 AN: 60262

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151920 Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1 AN XY: 74170

African (AFR) AF: 0.00 AC: 0 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15196

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
13	-	-	Hypercholesterolemia, familial, 1 (13)
4	-	-	Familial hypercholesterolemia (4)
4	-	-	not provided (4)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Dyslipidemia (1)
1	-	-	Homozygous familial hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	18
DANN	Benign	0.41
PhyloP100		-0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
Splicevardb		3.0
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		0.92		Position offset: 10

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

Other links and lift over

dbSNP: rs765696008; hg19: chr19-11223944;