rs786200869
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024884.3(L2HGDH):c.1115delT(p.Met372SerfsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,664 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
L2HGDH
NM_024884.3 frameshift
NM_024884.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.39
Publications
3 publications found
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 aciduriaInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
- mitochondrial diseaseInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 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 14-50265438-CA-C is Pathogenic according to our data. Variant chr14-50265438-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| L2HGDH | MANE Select | c.1115delT | p.Met372SerfsTer11 | frameshift | Exon 9 of 10 | NP_079160.1 | Q9H9P8-1 | ||
| L2HGDH | c.1115delT | p.Met372SerfsTer11 | frameshift | Exon 9 of 11 | NP_001412141.1 | Q9H9P8-1 | |||
| L2HGDH | c.1004delT | p.Met335SerfsTer11 | frameshift | Exon 10 of 12 | NP_001412142.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| L2HGDH | TSL:1 MANE Select | c.1115delT | p.Met372SerfsTer11 | frameshift | Exon 9 of 10 | ENSP00000267436.4 | Q9H9P8-1 | ||
| L2HGDH | TSL:1 | c.1115delT | p.Met372SerfsTer11 | frameshift | Exon 9 of 10 | ENSP00000261699.4 | C9JVN9 | ||
| L2HGDH | c.1238delT | p.Met413SerfsTer11 | frameshift | Exon 10 of 11 | ENSP00000559858.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460664Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726774 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1460664
Hom.:
Cov.:
30
AF XY:
AC XY:
1
AN XY:
726774
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33452
American (AMR)
AF:
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26122
East Asian (EAS)
AF:
AC:
0
AN:
39654
South Asian (SAS)
AF:
AC:
0
AN:
86226
European-Finnish (FIN)
AF:
AC:
0
AN:
53316
Middle Eastern (MID)
AF:
AC:
1
AN:
5764
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111046
Other (OTH)
AF:
AC:
0
AN:
60364
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
4
-
-
L-2-hydroxyglutaric aciduria (4)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
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
Publications
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