NM_002225.5:c.875T>C

Variant names:

• chr15-40414979-T-C
• rs1555404843
• NM_002225.5:c.875T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_002225.5(IVD):​c.875T>C​(p.Leu292Pro) 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 Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IVD NM_002225.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.79
• Publications: 0 publications found

Genes affected

IVD (HGNC:6186): (isovaleryl-CoA dehydrogenase) Isovaleryl-CoA dehydrogenase (IVD) is a mitochondrial matrix enzyme that catalyzes the third step in leucine catabolism. The genetic deficiency of IVD results in an accumulation of isovaleric acid, which is toxic to the central nervous system and leads to isovaleric acidemia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]

IVD Gene-Disease associations (from GenCC):

• isovaleric acidemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health, G2P, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_002225.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002225.5. 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
	IVD	NM_002225.5	MANE Select	c.875T>C	p.Leu292Pro	missense	Exon 8 of 12	NP_002216.3
	IVD	NM_001354601.3		c.875T>C	p.Leu292Pro	missense	Exon 8 of 12	NP_001341530.2
	IVD	NM_001354600.3		c.962T>C	p.Leu321Pro	missense	Exon 8 of 13	NP_001341529.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IVD	ENST00000487418.8	TSL:1 MANE Select	c.875T>C	p.Leu292Pro	missense	Exon 8 of 12	ENSP00000418397.3
	IVD	ENST00000479013.7	TSL:1	c.785T>C	p.Leu262Pro	missense	Exon 7 of 11	ENSP00000417990.3
	IVD	ENST00000868500.1		c.1028T>C	p.Leu343Pro	missense	Exon 9 of 13	ENSP00000538559.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Isovaleryl-CoA dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		5.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.79
MVP		0.95
MPC		1.2
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.95
Mutation Taster		=25/75	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: rs1555404843; hg19: chr15-40707178;