rs587778402

Variant names:

• chr2-208243503-A-C
• rs587778402
• NM_005896.4:c.622T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-208243503-A-C
• chr2-208243503-A-G

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.622T>G​(p.Tyr208Asp) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y208H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IDH1 NM_005896.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27
• Publications: 0 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, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDH1	NM_005896.4	c.622T>G	p.Tyr208Asp	missense_variant	Exon 6 of 10	ENST00000345146.7	NP_005887.2
IDH1	NM_001282386.1	c.622T>G	p.Tyr208Asp	missense_variant	Exon 6 of 10		NP_001269315.1
IDH1	NM_001282387.1	c.622T>G	p.Tyr208Asp	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.622T>G	p.Tyr208Asp	missense_variant	Exon 6 of 10	1	NM_005896.4	ENSP00000260985.2
IDH1	ENST00000415913.5	c.622T>G	p.Tyr208Asp	missense_variant	Exon 6 of 10	1		ENSP00000390265.1
IDH1	ENST00000446179.5	c.622T>G	p.Tyr208Asp	missense_variant	Exon 6 of 10	1		ENSP00000410513.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y208D variant (also known as c.622T>G), located in coding exon 4 of the IDH1 gene, results from a T to G substitution at nucleotide position 622. The tyrosine at codon 208 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;.;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.3	H;H;H
PhyloP100		9.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-9.2	D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.87
MutPred		0.70		Loss of catalytic residue at Y208 (P = 0.0055);Loss of catalytic residue at Y208 (P = 0.0055);Loss of catalytic residue at Y208 (P = 0.0055);
MVP		0.97
MPC		0.98
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.98
gMVP		0.95
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs587778402; hg19: chr2-209108227;