rs142761835

Positions:

chr15-40410699-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_002225.5(IVD):c.358G>A(p.Gly120Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

IVD
NM_002225.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.74

Variant links:

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 links:

IVD (HGNC:):

IVD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.893

PP5

Variant 15-40410699-G-A is Pathogenic according to our data. Variant chr15-40410699-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 167199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40410699-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IVD	NM_002225.5 linkuse as main transcript	c.358G>A	p.Gly120Arg	missense_variant	4/12	ENST00000487418.8	NP_002216.3	P26440A0A0A0MT83

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IVD	ENST00000487418.8 linkuse as main transcript	c.358G>A	p.Gly120Arg	missense_variant	4/12	1	NM_002225.5	ENSP00000418397.3		A0A0A0MT83

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251468

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000112

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.000410

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000801

Hom.:

Bravo

AF:

0.000136

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Isovaleryl-CoA dehydrogenase deficiency

Pathogenic:7

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Apr 04, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 30, 2023	Variant summary: IVD c.358G>A (p.Gly120Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251468 control chromosomes (gnomAD). c.358G>A (also known as c.367G>A, p.G123R) has been reported in the literature in multiple homozygous individuals affected with Isovaleryl-CoA Dehydrogenase Deficiency (examples: Carling_2018 and Dercksen_2012). At least one publication reports experimental evidence evaluating an impact on protein function. IVD enzyme activity from 10 homozygous individuals were below the quantification level (LOQ) of the validated assay (Dercksen_2012). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 13, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 29, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 123 of the IVD protein (p.Gly123Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with isovaleric acidemia (PMID: 22004070, 22350545, 27904153; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.358G>A (p.Gly91Arg). ClinVar contains an entry for this variant (Variation ID: 167199). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Gly123 amino acid residue in IVD. Other variant(s) that disrupt this residue have been observed in individuals with IVD-related conditions (PMID: 15486829), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 18, 2017	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2022	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as p.(G91R) or p.(G120R); This variant is associated with the following publications: (PMID: 25087612, 15486829, 22350545, 32778825, 28535199, 28631226, 27904153, 22004070, 31442447) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2024

The c.367G>A (p.G123R) alteration is located in exon 4 (coding exon 4) of the IVD gene. This alteration results from a G to an A substitution at nucleotide position 367, causing the glycine (G) at amino acid position 123 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of 0.004% (10/282872) total alleles studied. The highest observed frequency was 0.024% (6/24970) of African alleles. This alteration was detected in the homozygous state in multiple individuals with Isovaleric acidemia (Carling, 2018; Couce, 2017; Dercksen, 2012). This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

IVD-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2023

The IVD c.367G>A variant is predicted to result in the amino acid substitution p.Gly123Arg. This variant (also referred to in the literature as c.358G>A or p.Gly91Arg) has been reported with a second IVD variant or in the homozygous state in a number of individuals with isovaleric acidemia (Vatanavicharn et al. 2011. PubMed ID: 22004070; Dercksen et al. 2012. PubMed ID: 22350545; Couce et al. 2017. PubMed ID: 27904153; Carling et al. 2018. PubMed ID: 28631226). In fibroblasts from patients described by Derckesen et al. (2012), isovaleryl-CoA dehydrogenase activity was undetectable and protein levels were markedly reduced. We have also observed this variant internally in a number of presumably affected individuals. Based on these observations, we classify this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

.;D;.;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Pathogenic

1.0

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-5.1

.;D;D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

.;D;D;D

Sift4G

Uncertain

0.030

D;D;D;D

Vest4

0.83, 0.68

MVP

1.0

MPC

1.1

ClinPred

0.84

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over