rs879254692

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000527.5(LDLR):​c.826T>A​(p.Cys276Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,458,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C276G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

11
7
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.13
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 Pathogenic. Variant got 10 ACMG points.

PM1
In a domain LDL-receptor class A 7 (size 39) in uniprot entity LDLR_HUMAN there are 54 pathogenic changes around while only 7 benign (89%) in NM_000527.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-11107400-T-G is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDLRNM_000527.5 linkc.826T>A p.Cys276Ser missense_variant Exon 6 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.826T>A p.Cys276Ser missense_variant Exon 6 of 18 1 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1458940
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
725808
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.01e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
0.90
D;.;.;.;.;.
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D;D;D;D;D;D
M_CAP
Pathogenic
0.91
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.8
H;.;.;.;.;H
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-8.4
D;D;D;D;D;D
REVEL
Pathogenic
0.92
Sift
Uncertain
0.019
D;D;D;D;D;D
Sift4G
Uncertain
0.030
D;D;D;D;D;D
Polyphen
0.98
D;.;.;.;.;.
Vest4
0.97
MutPred
0.81
Gain of disorder (P = 0.0348);Gain of disorder (P = 0.0348);.;.;.;Gain of disorder (P = 0.0348);
MVP
1.0
MPC
0.85
ClinPred
1.0
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-11218076; API