19-11113588-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP4BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1412G>A (p.Arg471Lys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).BP4: REVEL = 0.412, it is below 0.50, splicing evaluation required.Functional data on splicing not available.A) variant not on limitsB) does not create AG or GTC) variant is exonic and there are 2 AG nearby;#1 MES scores: variant cryptic = -4.92, wt cryptic = -10.07, canonical acceptor= 6.76;#2 MES scores: variant cryptic = -7.95, wt cryptic = -13.41, canonical acceptor= 6.76.Scores are negative, so variant is not predicted to alter splicing.PP4: Variant meets PM2 and is identified in at least 1 case with definite FH by DLCN criteria from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583828.1), after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA404085845/MONDO:0007750/013

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:1B:1

Conservation

PhyloP100: 0.580

Publications

2 publications found

Variant links:

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 links:

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]

MIR6886 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

BP4

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LDLR	NM_000527.5	MANE Select	c.1412G>A	p.Arg471Lys	missense	Exon 10 of 18	NP_000518.1
LDLR	NM_001195798.2		c.1412G>A	p.Arg471Lys	missense	Exon 10 of 18	NP_001182727.1
LDLR	NM_001195799.2		c.1289G>A	p.Arg430Lys	missense	Exon 9 of 17	NP_001182728.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1412G>A	p.Arg471Lys	missense	Exon 10 of 18	ENSP00000454071.1
LDLR	ENST00000252444.10	TSL:1	c.1670G>A	p.Arg557Lys	missense	Exon 10 of 18	ENSP00000252444.6
LDLR	ENST00000558013.5	TSL:1	c.1412G>A	p.Arg471Lys	missense	Exon 10 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461754

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111972

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, familial, 1 (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Benign

-0.15

CADD

Benign

5.1

(source)

DANN

Benign

0.84

DEOGEN2

Uncertain

0.47

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.54

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.37

MutationAssessor

Benign

-1.1

PhyloP100

0.58

PrimateAI

Benign

0.26

PROVEAN

Benign

0.17

REVEL

Uncertain

0.41

Sift

Benign

0.15

Sift4G

Benign

0.84

Polyphen

0.0

Vest4

0.054

MutPred

0.46

Gain of ubiquitination at R471 (P = 0.0192)

MVP

0.99

MPC

0.21

ClinPred

0.034

GERP RS

-2.9

Varity_R

0.24

gMVP

0.86

Mutation Taster

=58/42

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over