rs1555328749
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_024884.3(L2HGDH):c.1015del(p.Arg339AspfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
L2HGDH
NM_024884.3 frameshift
NM_024884.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.66
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 14-50267801-CT-C is Pathogenic according to our data. Variant chr14-50267801-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 435701.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-50267801-CT-C is described in Lovd as [Pathogenic]. Variant chr14-50267801-CT-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
L2HGDH | NM_024884.3 | c.1015del | p.Arg339AspfsTer13 | frameshift_variant | 8/10 | ENST00000267436.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
L2HGDH | ENST00000267436.9 | c.1015del | p.Arg339AspfsTer13 | frameshift_variant | 8/10 | 1 | NM_024884.3 | P1 | |
L2HGDH | ENST00000261699.8 | c.1015del | p.Arg339AspfsTer13 | frameshift_variant | 8/10 | 1 | |||
L2HGDH | ENST00000421284.7 | c.1015del | p.Arg339AspfsTer13 | frameshift_variant | 8/11 | 2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
L-2-hydroxyglutaric aciduria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 13, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
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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