rs121434284

chr15-40405952-T-Achr15-40405952-T-Cchr15-40405952-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_002225.5(IVD):c.125T>A(p.Leu42Gln) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L42P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IVD NM_002225.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.39

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_002225.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-40405952-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 3562.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IVD	NM_002225.5	c.125T>A	p.Leu42Gln	missense_variant	1/12	ENST00000487418.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IVD	ENST00000487418.8	c.125T>A	p.Leu42Gln	missense_variant	1/12	1	NM_002225.5	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Isovaleryl-CoA dehydrogenase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 18, 2022

This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 45 of the IVD protein (p.Leu45Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IVD-related conditions. ClinVar contains an entry for this variant (Variation ID: 1440855). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	32
Dann	Uncertain	0.99
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
Sift4G	Uncertain	0.0050	D;D;T
Vest4		0.92, 0.61
MVP		0.91
MPC		1.1
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-40698153;