rs2229311

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_002225.5(IVD):c.149G>A(p.Arg50His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R50C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

IVD
NM_002225.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 9.03

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-40407639-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

PP5

Variant 15-40407640-G-A is Pathogenic according to our data. Variant chr15-40407640-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IVD	NM_002225.5 link	c.149G>A	p.Arg50His	missense_variant	2/12	ENST00000487418.8	NP_002216.3	P26440A0A0A0MT83

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IVD	ENST00000487418.8 link	c.149G>A	p.Arg50His	missense_variant	2/12	1	NM_002225.5	ENSP00000418397.3		A0A0A0MT83

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

251478

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461676

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

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

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Isovaleryl-CoA dehydrogenase deficiency

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 28, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 53 of the IVD protein (p.Arg53His). This variant is present in population databases (rs2229311, gnomAD 0.006%). This missense change has been observed in individual(s) with isovaleric acidemia (PMID: 15486829, 17027310, 19099814, 27904153). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.149G>A (p.Arg21His). ClinVar contains an entry for this variant (Variation ID: 370843). 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.Arg53 amino acid residue in IVD. Other variant(s) that disrupt this residue have been observed in individuals with IVD-related conditions (PMID: 10677295, 15486829, 17576084), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense c.149G>A (p.Arg50His) variant in the IVD gene has been observed in several patients with isovaleric acidemia (Ensenauer, Regina et al., 2004). The variant is present in a mutational hotspot. A different amino acid change p.Arg50Cys has been reported as pathogenic (van der Weerd K, et al., 2017). This variant is reported with the allele frequency (0.002%) in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic/Likely Pathogenic. The amino acid Arginine at position 50 is changed to a Histidine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Arg50His in IVD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2021

The c.158G>A (p.R53H) alteration is located in exon 2 (coding exon 2) of the IVD gene. This alteration results from a G to A substitution at nucleotide position 158, causing the arginine (R) at amino acid position 53 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (7/251478) total alleles studied. The highest observed frequency was 0.01% (2/34592) of Latino alleles. This alteration, also described as p.R21H in literature, has been reported in the homozygous state or compound heterozygous state with a second IVD alteration in several patients with isovaleric acidemia (Ensenauer, 2004; Lin, 2007; Couce, 2017; Li, 2019; Ibarra-González, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Sometimes reported as R21H or R50H using alternate nomenclature; This variant is associated with the following publications: (PMID: 25220015, 19099814, 15486829, 22960500, 33565069, 32778825, 32505769, 31442447, 27904153, 17027310, 31707166) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Pathogenic

0.93

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-4.5

.;D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

.;D;D

Sift4G

Uncertain

0.040

D;D;D

Vest4

0.90

MVP

0.98

MPC

1.2

ClinPred

0.98

GERP RS

5.3

Varity_R

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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