Variant 15-40407640-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_002225.5(IVD):c.149G>C(p.Arg50Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,461,676 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: not found (cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

IVD
NM_002225.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

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 16 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, 0.958

PP5

Variant 15-40407640-G-C is Pathogenic according to our data. Variant chr15-40407640-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40407640-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IVD	NM_002225.5 link	c.149G>C	p.Arg50Pro	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>C	p.Arg50Pro	missense_variant	2/12	1	NM_002225.5	ENSP00000418397.3		A0A0A0MT83

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251478

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000281

AC:

AN:

1461676

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

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:

0.0000333

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Isovaleryl-CoA dehydrogenase deficiency

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 13, 2020	This sequence change replaces arginine with proline at codon 53 of the IVD protein (p.Arg53Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs2229311, ExAC 0.02%). This variant has been observed in individual(s) with isovaleric acidemia (PMID: 27904153, 26018748, 9665741). This variant is also known as p.Arg21Pro in the literature. ClinVar contains an entry for this variant (Variation ID: 188922). This variant has been reported to affect IVD protein function (PMID: 9665741). This variant disrupts the p.Arg53 amino acid residue in IVD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 110677295). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Aug 19, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 27, 2023	Variant summary: IVD c.149G>C (p.Arg50Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251478 control chromosomes (gnomAD). c.149G>C has been reported in the literature in individuals affected with Isovaleryl-CoA Dehydrogenase Deficiency (examples: Mohsen_1998, Ensenauer_2004, and Couce_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Mohsen_1998). The following publications have been ascertained in the context of this evaluation (PMID: 27904153, 15486829, 9665741). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 29, 2021	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2018	- -

IVD-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2024

The IVD c.158G>C variant is predicted to result in the amino acid substitution p.Arg53Pro. This variant, alternately described in the literature as Arg21Pro or c.149G>C, p.Arg50Pro, has been recurrently reported in patients with isovaleric acidemia and has been reported to impact protein function (Mohsen et al. 1998. PubMed ID: 9665741; Ensenauer et al. 2004. PubMed ID: 15486829; Sakamoto et al. 2015. PubMed ID: 26018748; Couce et al. 2016. PubMed ID: 27904153; D'Annibale et al. 2021. PubMed ID: 34535384; Mütze et al. 2021. PubMed ID: 33496032). Different substitutions of the same amino acid (p.Arg53Cys, p.Arg53His, p.Arg53Leu) have also been reported in isovaleric acidemia patients (Ensenauer et al. 2004. PubMed ID: 15486829; Lee et al. 2007. PubMed ID: 17576084; Li et al. 2019. PubMed ID: 31442447). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

0.92

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-6.3

.;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.98

MVP

0.95

MPC

1.3

ClinPred

1.0

GERP RS

5.3

Varity_R

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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