rs746518411
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_003383.5(VLDLR):c.1667G>A(p.Arg556Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000122 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
VLDLR
NM_003383.5 missense
NM_003383.5 missense
Scores
5
14
Clinical Significance
Conservation
PhyloP100: 5.57
Genes affected
VLDLR (HGNC:12698): (very 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. This gene encodes a lipoprotein receptor that is a member of the LDLR family and plays important roles in VLDL-triglyceride metabolism and the reelin signaling pathway. Mutations in this gene cause VLDLR-associated cerebellar hypoplasia. Alternative splicing generates multiple transcript variants encoding distinct isoforms for this gene. [provided by RefSeq, Aug 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.14519677).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VLDLR | NM_003383.5 | c.1667G>A | p.Arg556Gln | missense_variant | 11/19 | ENST00000382100.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VLDLR | ENST00000382100.8 | c.1667G>A | p.Arg556Gln | missense_variant | 11/19 | 1 | NM_003383.5 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 152146Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000183 AC: 46AN: 251376Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135854
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GnomAD4 exome AF: 0.000123 AC: 180AN: 1461854Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 89AN XY: 727224
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GnomAD4 genome ? AF: 0.000112 AC: 17AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74320
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 01, 2016 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 19, 2023 | The c.1667G>A (p.R556Q) alteration is located in exon 11 (coding exon 11) of the VLDLR gene. This alteration results from a G to A substitution at nucleotide position 1667, causing the arginine (R) at amino acid position 556 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 19, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 556 of the VLDLR protein (p.Arg556Gln). This variant is present in population databases (rs746518411, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with VLDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 437222). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant in c.1667G>A(p.Arg556Gln) in VLDLR gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Arg556Gln variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.02% in gnomAD database. This variant has been reported to the ClinVar database as Variant of Uncertain Significance (VUS). The amino acid change p.Arg556Gln in VLDLR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 556 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
N;N
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MutPred
Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at