19-11113346-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):​c.1255T>G​(p.Tyr419Asp) variant causes a missense change. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y419H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 29)

Consequence

LDLR
NM_000527.5 missense

Scores

11
7
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.18
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 Pathogenic. Variant got 18 ACMG points.

PM1
In a repeat LDL-receptor class B 1 (size 41) in uniprot entity LDLR_HUMAN there are 61 pathogenic changes around while only 8 benign (88%) 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 chr19-11113346-T-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.951
PP5
Variant 19-11113346-T-G is Pathogenic according to our data. Variant chr19-11113346-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 369853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LDLRNM_000527.5 linkc.1255T>G p.Tyr419Asp missense_variant 9/18 ENST00000558518.6 NP_000518.1 P01130-1A0A024R7D5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkc.1255T>G p.Tyr419Asp missense_variant 9/181 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
Cov.:
29
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
29

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingU4M - Lille University & CHRU Lille, Université de Lille - CHRU de LilleMar 30, 2017- -
Likely pathogenic, criteria provided, single submitterclinical testingRobarts Research Institute, Western University-- -
Familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 18, 2023This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 419 of the LDLR protein (p.Tyr419Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with LDLR-related conditions (PMID: 27765764, 30270081, 33303402, 33740630). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 369853). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.89
D;.;.;.;.;.
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.95
D;D;D;D;D;D
M_CAP
Pathogenic
0.86
D
MetaRNN
Pathogenic
0.95
D;D;D;D;D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Uncertain
2.5
M;.;.;.;.;M
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-9.8
D;D;D;D;D;D
REVEL
Pathogenic
0.83
Sift
Uncertain
0.0010
D;D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D
Polyphen
0.99
D;.;.;.;.;.
Vest4
0.86
MutPred
0.65
Gain of disorder (P = 0.007);Gain of disorder (P = 0.007);.;.;.;Gain of disorder (P = 0.007);
MVP
1.0
MPC
1.1
ClinPred
1.0
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.96
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: rs879254847; hg19: chr19-11224022; API