rs142761835

chr15-40410699-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_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. 11/18 in silico tools predict a damaging 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. G120E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: IVD NM_002225.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.74

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr15-40410700-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2736174.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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	UniProt
IVD	NM_002225.5	c.358G>A	p.Gly120Arg	missense_variant	4/12	ENST00000487418.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IVD	ENST00000487418.8	c.358G>A	p.Gly120Arg	missense_variant	4/12	1	NM_002225.5	P4

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152182 Hom.: 0 Cov.: 33

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: 7 AN: 251468 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135918

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: 27 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 727248

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: 17 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74338

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.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

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	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 03, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 18, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -

not provided Pathogenic:2

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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -

IVD-related condition 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	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.53	T
Sift4G	Uncertain	0.030	D;D;D;D
Vest4		0.83, 0.68
MVP		1.0
MPC		1.1
ClinPred		0.84	D
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

Other links and lift over

dbSNP: rs142761835; hg19: chr15-40702898;