rs879254383
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_000527.5(LDLR):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Genomes: not found (cov: 32)
Consequence
LDLR
NM_000527.5 start_lost
NM_000527.5 start_lost
Scores
7
4
4
Clinical Significance
Conservation
PhyloP100: 2.42
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 Pathogenic. Variant got 20 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_000527.5 (LDLR) was described as [Likely_pathogenic] in ClinVar as 250969
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-11089551-G-A is Pathogenic according to our data. Variant chr19-11089551-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 440536.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.3G>A | p.Met1? | start_lost | 1/18 | ENST00000558518.6 | |
LDLR-AS1 | NR_163945.1 | n.109C>T | non_coding_transcript_exon_variant | 1/1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.3G>A | p.Met1? | start_lost | 1/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Jan 22, 2022 | The NM_000527.5(LDLR):c.3G>A (p.Met1Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PVS1_Moderate, and PM5 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - variant is absent from gnomAD (v2.1.1). PVS1_Moderate – variant is predicted to affect the initiation codon. PM5- Three other missense variants at this same codon have been reported, and one is Pathogenic: 1) NM_000527.5(LDLR):c.1A>C (p.Met1Leu) – Pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1A>G (p.Met1Val) - Likely pathogenic by these guidelines. 3) NM_000527.4(LDLR):c.2T>C (p.Met1Thr) - Likely pathogenic by these guidelines. Note: One other variant resulting in the same amino acid change at this codon has been reported: 1) NM_000527.5(LDLR):c.3G>T (p.Met1Ile) - Likely pathogenic by these guidelines. -PS1 not applicable as such variants must be Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Uncertain
D;.;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D
PROVEAN
Benign
N;N;N;N;N;N
Sift
Pathogenic
D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
P;.;.;.;.;.
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0444);Gain of catalytic residue at M1 (P = 0.0444);Gain of catalytic residue at M1 (P = 0.0444);Gain of catalytic residue at M1 (P = 0.0444);Gain of catalytic residue at M1 (P = 0.0444);Gain of catalytic residue at M1 (P = 0.0444);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at