19-11111644-G-C

Variant names:

• chr19-11111644-G-C
• rs879254821
• NM_000527.5:c.1186+5G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.1186+5G>C variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4) 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: PopMaxMAF = 0.0000809 in African/African American population in gnomAD (gnomAD v2.1.1).The PopMax is African/African American for this variant. However the allele number at this position for 19-11222320-G-C is 2 / 8710, which is < 10,000 in total and only genome data is available. Exome data from a neighboring variant 19-11222323-C-T, allele number 15994, was used for PopMaxMAF calculation:PopMaxMAF = 2 / (15994 + 8710) = 0.0000809 in African/African American populationPP3: Variant is located within canonical intron 8 donor motif, splicing prediction is performed using MES: Wild type canonical donor motif tggGTGAGC score = 7.23, Variant canonical donor motif tggGTGACC score = 0.50, Var Score/Wt Score Ratio = 0.0692 which is <0.8, therefore PP3 is met. Predicted impact for alternative splicing caused by this variant is also confirmed by SpliceAI.PP4: Variant meets PM2 and is identified in 1 index case who fulfil Simon Broome criteria for possible FH and DLCN score = 6 (PMID 32220565, Table 2), after alternative causes of high cholesterol were excluded, reported by Brown et al, 2020, from Johns Hopkins University, US.PS3 not met: Functional data is not available. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16602324/MONDO:0007750/013

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 31)
• Consequence: LDLR NM_000527.5 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:6
• Conservation: PhyloP100: 5.28
• 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1186+5G>C		splice_region intron	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1186+5G>C		splice_region intron	N/A	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1063+5G>C		splice_region 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.1186+5G>C		splice_region intron	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1444+5G>C		splice_region intron	N/A	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1186+5G>C		splice_region intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000482

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74370

African (AFR) AF: 0.0000482 AC: 2 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	3	-	Hypercholesterolemia, familial, 1 (4)
-	1	-	Cardiovascular phenotype (1)
1	-	-	Dyslipidemia (1)
-	1	-	Familial hypercholesterolemia (1)
1	-	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	33
DANN	Benign	0.80
PhyloP100		5.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.93		Position offset: -9
DS_DL_spliceai		0.78		Position offset: -5

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

Other links and lift over

dbSNP: rs879254821; hg19: chr19-11222320;