19-11116901-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5PM2PP3PP4

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1748A>G (p.His583Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.819. PM5: There is 1 variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) (ClinVar ID: 200921).PP4: Variant meets PM2 and is identified in at least 1 index case with possible FH by Simon Broome criteria, after alternative causes of high cholesterol were excluded, from the Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic (PMID 22698793, TichĂ˝ et al., 2012). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585595/MONDO:0007750/013

Frequency

Genomes: not found (cov: 32)
Exomes đť‘“: 6.8e-7 ( 0 hom. )

Consequence

LDLR
ENST00000558518.6 missense

Scores

9
8
2

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 6.21
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM5
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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LDLRNM_000527.5 linkuse as main transcriptc.1748A>G p.His583Arg missense_variant 12/18 ENST00000558518.6 NP_000518.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkuse as main transcriptc.1748A>G p.His583Arg missense_variant 12/181 NM_000527.5 ENSP00000454071 P3P01130-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461788
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
727202
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.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, Centre for Cardiovascular Surgery and TransplantationNov 05, 2016- -
Likely pathogenic, criteria provided, single submitterliterature onlyLDLR-LOVD, British Heart FoundationMar 25, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.39
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
D;.;.;.;.;.
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
D;D;D;D;D;D
M_CAP
Pathogenic
0.61
D
MetaRNN
Pathogenic
0.77
D;D;D;D;D;D
MetaSVM
Uncertain
0.78
D
MutationAssessor
Uncertain
2.1
M;.;.;.;.;M
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-7.9
D;D;D;D;D;D
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0010
D;D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D
Polyphen
1.0
D;.;.;.;.;.
Vest4
0.43
MutPred
0.59
Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);.;.;.;Gain of sheet (P = 0.0149);
MVP
1.0
MPC
0.88
ClinPred
1.0
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.94
gMVP
0.99

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.

Other links and lift over

dbSNP: rs879255007; hg19: chr19-11227577; API