19-11113280-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000527.5(LDLR):ā€‹c.1189T>Cā€‹(p.Ser397Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S397F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense, splice_region

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.40
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1
In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000527.5
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.19393814).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LDLRNM_000527.5 linkuse as main transcriptc.1189T>C p.Ser397Pro missense_variant, splice_region_variant 9/18 ENST00000558518.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LDLRENST00000558518.6 linkuse as main transcriptc.1189T>C p.Ser397Pro missense_variant, splice_region_variant 9/181 NM_000527.5 P3P01130-1

Frequencies

GnomAD3 genomes
Cov.:
29
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460444
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
726532
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
29

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial hypercholesterolemia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthOct 23, 2019This missense variant (also known as p.Ser376Pro in the mature protein) replaces serine with proline at codon 397 of the LDLR protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.0
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.55
D;.;.;.;.;.
Eigen
Benign
-0.77
Eigen_PC
Benign
-0.65
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.74
T;T;T;T;T;T
M_CAP
Uncertain
0.23
D
MetaRNN
Benign
0.19
T;T;T;T;T;T
MetaSVM
Benign
-0.64
T
MutationAssessor
Benign
-0.15
N;.;.;.;.;N
MutationTaster
Benign
0.75
D;D;D;D;D;D;D
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-2.1
N;N;N;N;N;N
REVEL
Uncertain
0.50
Sift
Benign
0.037
D;T;T;D;T;D
Sift4G
Benign
0.19
T;T;T;T;T;T
Polyphen
0.0
B;.;.;.;.;.
Vest4
0.12
MutPred
0.60
Loss of catalytic residue at S397 (P = 0.0281);Loss of catalytic residue at S397 (P = 0.0281);.;.;.;Loss of catalytic residue at S397 (P = 0.0281);
MVP
1.0
MPC
0.27
ClinPred
0.14
T
GERP RS
2.8
Varity_R
0.36
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs879254825; hg19: chr19-11223956; API