rs786200869
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_024884.3(L2HGDH):c.1115del(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 (★★).
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
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 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
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 id is 1608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
L2HGDH | NM_024884.3 | c.1115del | p.Met372SerfsTer11 | frameshift_variant | 9/10 | ENST00000267436.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
L2HGDH | ENST00000267436.9 | c.1115del | p.Met372SerfsTer11 | frameshift_variant | 9/10 | 1 | NM_024884.3 | P1 | |
L2HGDH | ENST00000261699.8 | c.1115del | p.Met372SerfsTer11 | frameshift_variant | 9/10 | 1 | |||
L2HGDH | ENST00000421284.7 | c.1115del | p.Met372SerfsTer11 | frameshift_variant | 9/11 | 2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
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
GnomAD4 exome
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1460664
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30
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1
AN XY:
726774
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GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
L-2-hydroxyglutaric aciduria Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 15, 2004 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 01, 2020 | Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PVS1,PM2,PM3,PP1 - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 07, 2017 | - - |
Computational scores
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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