rs17248882

Variant names:

• chr19-11116849-G-A
• rs17248882
• NM_000527.5:c.1706-10G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. BS1 PP1_Moderate BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1706-10G>A variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes BS1, BS3_supporting and PP1_moderate 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:BS1 - FAF = 0.002911 (0.2911%) in Latino/Admixed American exomes (gnomAD v2.1.1), so BS1 is Met.BS3_supporting - 2 Level 3 assays: PMID:25741862: Heterozygous patients' lymphocytes, RNA assays - result - Normal LDLR transcripts identified by sequencing.PMID:19208450: Heterozygous patients' Epstein Barr virus transformed lymphocytes, RNA assays - result - Normal LDLR transcripts, 43% of mutant transcripts (from total transcripts) in htz cells.---- Aberrant transcripts are not detected, so BS3_Supporting is Met.PP1_moderate - Variant segregates with FH phenotype in at least 5 informative meiosis from 2 families from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge: 5 affected family members have the variant, so PP1_Moderate is Met.Variant has 1 Strong plus 1 Supporting evidence codes towards Benign, enough to classify as Likely benign and only 1 Moderate evidence code towards Pathogenic, not enough for Likely pathogenic, so we are confident in classifying this variant as Likely benign. LINK:https://erepo.genome.network/evrepo/ui/classification/CA035940/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (8 hom.)
• Consequence: LDLR NM_000527.5 intron
• Scores: Splicing: ADA: 0.001607
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:27
• Conservation: PhyloP100: -0.240
• Publications: 11 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: Likely_benign. The variant received -3 ACMG points.

• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.1706-10G>A		intron	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1706-10G>A		intron	N/A	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1583-10G>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.1706-10G>A		intron	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1964-10G>A		intron	N/A	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1706-10G>A		intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152182 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00302

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00225

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00232 AC: 584 AN: 251472 AF XY: 0.00247

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00274

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00199 AC: 2901 AN: 1461206 Hom.: 8 Cov.: 34 AF XY: 0.00204 AC XY: 1481 AN XY: 726904

African (AFR) AF: 0.000388 AC: 13 AN: 33468

American (AMR) AF: 0.00344 AC: 154 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00402 AC: 105 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00276 AC: 238 AN: 86210

European-Finnish (FIN) AF: 0.000618 AC: 33 AN: 53394

Middle Eastern (MID) AF: 0.0127 AC: 67 AN: 5294

European-Non Finnish (NFE) AF: 0.00192 AC: 2131 AN: 1111952

Other (OTH) AF: 0.00265 AC: 160 AN: 60336

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152300 Hom.: 1 Cov.: 33 AF XY: 0.00154 AC XY: 115 AN XY: 74476

African (AFR) AF: 0.000192 AC: 8 AN: 41562

American (AMR) AF: 0.00301 AC: 46 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00225 AC: 153 AN: 68036

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00190 Hom.: 0

Bravo AF: 0.00185

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	3	13	Hypercholesterolemia, familial, 1 (16)
-	-	5	not provided (5)
-	-	4	Familial hypercholesterolemia (4)
-	-	4	not specified (4)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.2
DANN	Benign	0.74
PhyloP100		-0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0016
dbscSNV1_RF	Benign	0.41
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs17248882; hg19: chr19-11227525;