chr19-11123329-A-G

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.2296A>G (p.Thr766Ala) 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 28 October 2024.The supporting evidence is as follows: PM2: PopMax MAF= 0.00001600 (0.0016%) in Remaining group exomes (gnomAD v4.1.0).BP4: REVEL=0.481. it is below 0.50, splicing evaluation required.Functional data on splicing not available.A) variant not on limits.B) variant is exonic and at least 50bp downstream from the canonical acceptor site, but it does not create GT.C) there is a GT nearby.MES scores: variant cryptic = -26.75, wt cryptic = -35.70, canonical donor = 9.06.Scores are negative, splice site not used. Variant is not predicted to alter splicing. PP4: Variant meets PM2 and is identified in 1 case who fulfills Simon Broome criteria for possible FH after alternative causes of high cholesterol excluded, in PMID 20236128 (Taylor et al., 2010), UK. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585815/MONDO:0007750/013

Frequency

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

Consequence

LDLR
NM_000527.5 missense

Scores

2
8
9

Clinical Significance

Uncertain significance reviewed by expert panel U:2

Conservation

PhyloP100: 2.14

Publications

1 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 Gene-Disease associations (from GenCC):
  • hypercholesterolemia, familial, 1
    Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
  • homozygous familial hypercholesterolemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDLRNM_000527.5 linkc.2296A>G p.Thr766Ala missense_variant Exon 15 of 18 ENST00000558518.6 NP_000518.1 P01130-1A0A024R7D5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkc.2296A>G p.Thr766Ala missense_variant Exon 15 of 18 1 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461812
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
727200
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53390
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111968
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60394
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:2
Oct 28, 2024
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
Significance:Uncertain significance
Review Status:reviewed by expert panel
Collection Method:curation

The NM_000527.5(LDLR):c.2296A>G (p.Thr766Ala) 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 28 October 2024. The supporting evidence is as follows: PM2: PopMax MAF= 0.00001600 (0.0016%) in Remaining group exomes (gnomAD v4.1.0). BP4: REVEL=0.481. it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp downstream from the canonical acceptor site, but it does not create GT. C) there is a GT nearby. MES scores: variant cryptic = -26.75, wt cryptic = -35.70, canonical donor = 9.06. Scores are negative, splice site not used. Variant is not predicted to alter splicing. PP4: Variant meets PM2 and is identified in 1 case who fulfills Simon Broome criteria for possible FH after alternative causes of high cholesterol excluded, in PMID 20236128 (Taylor et al., 2010), UK. -

Mar 25, 2016
LDLR-LOVD, British Heart Foundation
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.010
CADD
Benign
16
DANN
Benign
0.93
DEOGEN2
Uncertain
0.61
D;.;.;.;.;.
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.38
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Benign
0.63
T;T;T;T;T;T
M_CAP
Pathogenic
0.56
D
MetaRNN
Benign
0.39
T;T;T;T;T;T
MetaSVM
Uncertain
-0.21
T
MutationAssessor
Uncertain
2.4
M;.;.;.;.;M
PhyloP100
2.1
PrimateAI
Benign
0.41
T
PROVEAN
Uncertain
-2.6
D;D;N;D;D;D
REVEL
Uncertain
0.48
Sift
Benign
0.095
T;T;T;T;T;T
Sift4G
Uncertain
0.056
T;T;T;T;D;T
Polyphen
0.97
D;.;.;.;.;.
Vest4
0.15
MutPred
0.48
Loss of glycosylation at T766 (P = 0.0131);Loss of glycosylation at T766 (P = 0.0131);.;.;.;Loss of glycosylation at T766 (P = 0.0131);
MVP
1.0
MPC
0.23
ClinPred
0.86
D
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.14
gMVP
0.80
Mutation Taster
=18/82
disease causing

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

Other links and lift over

dbSNP: rs879255171; hg19: chr19-11234005; API