2-208248389-G-T
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PM5PP3PP5_Moderate
The NM_005896.4(IDH1):c.394C>A(p.Arg132Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R132G) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
IDH1
NM_005896.4 missense
NM_005896.4 missense
Scores
15
3
Clinical Significance
Conservation
PhyloP100: 7.10
Publications
1100 publications found
Genes affected
IDH1 (HGNC:5382): (isocitrate dehydrogenase (NADP(+)) 1) Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer. The protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2, 4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2013]
IDH1 Gene-Disease associations (from GenCC):
- Maffucci syndromeInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-208248389-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 375891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 2-208248389-G-T is Pathogenic according to our data. Variant chr2-208248389-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 375893.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_005896.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| IDH1 | NM_005896.4 | MANE Select | c.394C>A | p.Arg132Ser | missense | Exon 4 of 10 | NP_005887.2 | ||
| IDH1 | NM_001282386.1 | c.394C>A | p.Arg132Ser | missense | Exon 4 of 10 | NP_001269315.1 | |||
| IDH1 | NM_001282387.1 | c.394C>A | p.Arg132Ser | missense | Exon 4 of 10 | NP_001269316.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| IDH1 | ENST00000345146.7 | TSL:1 MANE Select | c.394C>A | p.Arg132Ser | missense | Exon 4 of 10 | ENSP00000260985.2 | ||
| IDH1 | ENST00000415913.5 | TSL:1 | c.394C>A | p.Arg132Ser | missense | Exon 4 of 10 | ENSP00000390265.1 | ||
| IDH1 | ENST00000446179.5 | TSL:1 | c.394C>A | p.Arg132Ser | missense | Exon 4 of 10 | ENSP00000410513.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461688Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727166
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1461688
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
727166
African (AFR)
AF:
AC:
0
AN:
33472
American (AMR)
AF:
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26134
East Asian (EAS)
AF:
AC:
0
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86242
European-Finnish (FIN)
AF:
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111856
Other (OTH)
AF:
AC:
0
AN:
60380
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic
Revision:criteria provided, single submitter