Variant 19-11113588-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PP5_ModerateBP4

The NM_000527.5(LDLR):c.1412G>A(p.Arg471Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R471G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1B:1

Conservation

PhyloP100: 0.580

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in NM_000527.5

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-11113588-G-A is Pathogenic according to our data. Variant chr19-11113588-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430776.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.11527738). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.1412G>A	p.Arg471Lys	missense_variant	10/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1412G>A	p.Arg471Lys	missense_variant	10/18	1	NM_000527.5	P3	P01130-1

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:1Benign:1

Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Benign

-0.15

CADD

Benign

5.1

DANN

Benign

0.84

DEOGEN2

Uncertain

0.47

T;.;.;.;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.54

T;T;T;T;T;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.12

T;T;T;T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

-1.1

N;.;.;.;.;N

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

0.17

N;N;N;N;N;N

REVEL

Uncertain

0.41

Sift

Benign

0.15

T;T;T;T;T;T

Sift4G

Benign

0.84

T;T;T;T;T;T

Polyphen

0.0

B;.;.;.;.;.

Vest4

0.054

MutPred

0.46

Gain of ubiquitination at R471 (P = 0.0192);Gain of ubiquitination at R471 (P = 0.0192);.;.;.;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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over