NM_005896.4:c.665G>T

Variant names:

• chr2-208243460-C-A
• rs587778401
• NM_005896.4:c.665G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005896.4(IDH1):​c.665G>T​(p.Arg222Leu) 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 not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R222H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IDH1 NM_005896.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 6.13
• Publications: 4 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 syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDH1	NM_005896.4	c.665G>T	p.Arg222Leu	missense_variant	Exon 6 of 10	ENST00000345146.7	NP_005887.2
IDH1	NM_001282386.1	c.665G>T	p.Arg222Leu	missense_variant	Exon 6 of 10		NP_001269315.1
IDH1	NM_001282387.1	c.665G>T	p.Arg222Leu	missense_variant	Exon 6 of 10		NP_001269316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDH1	ENST00000345146.7	c.665G>T	p.Arg222Leu	missense_variant	Exon 6 of 10	1	NM_005896.4	ENSP00000260985.2
IDH1	ENST00000415913.5	c.665G>T	p.Arg222Leu	missense_variant	Exon 6 of 10	1		ENSP00000390265.1
IDH1	ENST00000446179.5	c.665G>T	p.Arg222Leu	missense_variant	Exon 6 of 10	1		ENSP00000410513.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	.;.;D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.2	M;M;M
PhyloP100		6.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.9	D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.093	T;T;T
Polyphen		0.96	D;D;D
Vest4		0.89
MutPred		0.66		Loss of methylation at R222 (P = 0.0159);Loss of methylation at R222 (P = 0.0159);Loss of methylation at R222 (P = 0.0159);
MVP		0.93
MPC		0.26
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.88
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587778401; hg19: chr2-209108184;