GeneBe

rs797045677

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_024884.3(L2HGDH):​c.460G>C​(p.Glu154Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

L2HGDH
NM_024884.3 missense

Scores

6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.17

Publications

0 publications found
Variant links:
Genes affected
L2HGDH (HGNC:20499): (L-2-hydroxyglutarate dehydrogenase) This gene encodes L-2-hydroxyglutarate dehydrogenase, a FAD-dependent enzyme that oxidizes L-2-hydroxyglutarate to alpha-ketoglutarate in a variety of mammalian tissues. Mutations in this gene cause L-2-hydroxyglutaric aciduria, a rare autosomal recessive neurometabolic disorder resulting in moderate to severe cognitive disability. [provided by RefSeq, Jul 2008]
L2HGDH Gene-Disease associations (from GenCC):
  • L-2-hydroxyglutaric aciduria
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
  • mitochondrial disease
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.32780707).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024884.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
L2HGDH
NM_024884.3
MANE Select
c.460G>Cp.Glu154Gln
missense
Exon 4 of 10NP_079160.1Q9H9P8-1
L2HGDH
NM_001425212.1
c.460G>Cp.Glu154Gln
missense
Exon 4 of 11NP_001412141.1Q9H9P8-1
L2HGDH
NM_001425213.1
c.349G>Cp.Glu117Gln
missense
Exon 5 of 12NP_001412142.1

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
L2HGDH
ENST00000267436.9
TSL:1 MANE Select
c.460G>Cp.Glu154Gln
missense
Exon 4 of 10ENSP00000267436.4Q9H9P8-1
L2HGDH
ENST00000261699.8
TSL:1
c.460G>Cp.Glu154Gln
missense
Exon 4 of 10ENSP00000261699.4C9JVN9
L2HGDH
ENST00000555423.5
TSL:1
c.460G>Cp.Glu154Gln
missense
Exon 4 of 6ENSP00000450494.1G3V272

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

ClinVar submissions
Significance:Uncertain significance
Revision:criteria provided, single submitter
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
1
-
not specified (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.016
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.16
T
Eigen
Benign
0.14
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.90
D
M_CAP
Benign
0.036
D
MetaRNN
Benign
0.33
T
MetaSVM
Uncertain
-0.24
T
MutationAssessor
Benign
1.3
L
PhyloP100
3.2
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-1.8
N
REVEL
Uncertain
0.34
Sift
Benign
0.27
T
Sift4G
Benign
0.27
T
Polyphen
0.77
P
Vest4
0.17
MutPred
0.43
Loss of ubiquitination at K155 (P = 0.0547)
MVP
0.75
MPC
0.32
ClinPred
0.84
D
GERP RS
4.3
Varity_R
0.30
gMVP
0.60
Mutation Taster
=72/28
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs797045677; hg19: chr14-50760913; API