rs28940889

chr15-40415454-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_002225.5(IVD):c.932C>T(p.Ala311Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000901 in 1,614,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00092 (0 hom.)
• Consequence: IVD NM_002225.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 7.36

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 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-40415454-C-T is Pathogenic according to our data. Variant chr15-40415454-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 100060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40415454-C-T is described in Lovd as [Pathogenic]. Variant chr15-40415454-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.2668892).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IVD	NM_002225.5	c.932C>T	p.Ala311Val	missense_variant	9/12	ENST00000487418.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IVD	ENST00000487418.8	c.932C>T	p.Ala311Val	missense_variant	9/12	1	NM_002225.5	P4

Frequencies

GnomAD3 genomes AF: 0.000729 AC: 111 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000641 AC: 161 AN: 251360 Hom.: 0 AF XY: 0.000640 AC XY: 87 AN XY: 135866

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000919 AC: 1344 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.000925 AC XY: 673 AN XY: 727218

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000729 AC: 111 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000725 AC XY: 54 AN XY: 74480

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000961 Hom.: 0

Bravo AF: 0.000657

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000725 AC: 88

EpiCase AF: 0.000763

EpiControl AF: 0.000948

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Isovaleryl-CoA dehydrogenase deficiency Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 21, 2023	Variant summary: IVD c.932C>T (p.Ala311Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00064 in 251360 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in IVD causing Isovaleryl-CoA Dehydrogenase Deficiency (0.00064 vs 0.0022), allowing no conclusion about variant significance. c.932C>T has been reported in the literature in multiple individuals affected with a milder/subclinical presentation of Isovaleryl-CoA Dehydrogenase Deficiency/Isovaleric acidemia (IVA) (example, PMID: 27904153, 15486829, 9665741). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in vitro (PMID: 9665741). The most pronounced variant effect results in <3% of normal catalytic efficiency per mole of flavin adenine dinucleotide (FAD) content and 19% of wild type Isovaleryl-CoA dehydrogenase (IVD) enzyme activity. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories 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	Fulgent Genetics, Fulgent Genetics	Mar 02, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 11, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 314 of the IVD protein (p.Ala314Val). This variant is present in population databases (rs28940889, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with NBS or mild elevations of isovaleric acidemia-related metabolites and residual IVD enzyme activity (PMID: 15486829). 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 p.Ala282Val. ClinVar contains an entry for this variant (Variation ID: 100060). 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. Experimental studies have shown that this missense change affects IVD function (PMID: 9665741). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 13, 2019	NM_002225.3(IVD):c.941C>T(A314V, aka A311V) is classified as pathogenic in the context of isovaleric acidemia. Please note that individuals with the A314V variant may have a mild form of isovaleric acidemia or may be asymptomatic. Sources cited for classification include the following: PMID 15486829, 15337167 and 9665741. Classification of NM_002225.3(IVD):c.941C>T(A314V, aka A311V) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 01, 2023	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	IVD: PM3:Strong, PM1, PM2, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 20, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2021	Reported in association with isovaleric acidemia (IVA) and has been found in a homozygous or compound heterozygous state with another IVD pathogenic variant in approximately two-thirds of newborns with IVA diagnosed by newborn screening (Ensenauer et al., 2004); Thus far, all of the newborns harboring A314V, including compound heterozygotes for this variant, have a mild biochemical phenotype and have remained asymptomatic with no or limited treatment (Ensenauer et al., 2004); Published functional studies demonstrate A314V results in reduced isovaleryl-CoA dehydrogenase activity compared to wild-type (Mohsen et al. 1998); This variant is associated with the following publications: (PMID: 26937393, 16602101, 27904153, 25087612, 22995991, 9665741, 15486829, 15337167, 22960500, 26018748, 31980526, 28631226, 29431110, 31707166, 34426522, 32778825, 27535533, 24077912) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 13, 2020	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2021

The c.941C>T (p.A314V) alteration is located in exon 9 (coding exon 9) of the IVD gene. This alteration results from a C to T substitution at nucleotide position 941, causing the alanine (A) at amino acid position 314 to be replaced by a valine (V). Based on data from the Genome Aggregation Database (gnomAD) database, the IVD c.941C>T alteration was observed in 0.07% (184/282758) of total alleles studied, with a frequency of 0.12% (156/129130) in the European (non-Finnish) subpopulation. This alteration (referred to as A282V in some publications) has been reported in the homozygous and compound heterozygous states in many individuals with isovaleric acidemia (IVA) (Ensenauer, 2004; Lambrecht, 2015; Mütze, 2021; Szymaska, 2020; Tangeraas, 2020). Most patients are reported to have mild elevation of isovalerylcarnitine, but are clinically asymptomatic (Ensenauer, 2004; Lambrecht, 2015; Mütze, 2021). A few patients have been reported with a mild symptomatic form of IVA (Mütze, 2021; Szymaska, 2020). The p.A314 amino acid is conserved in available vertebrate species. When expressed in E. coli, this alteration was shown to result in a less stable protein which was catalytically less efficient as compared to wild-type (Mohsen, 1998). Biochemical studies using lymphocytes and fibroblasts from patients homozygous for this alteration showed accumulation of isovalerylcarnitine in the cell medium, but at levels lower than patients with other known pathogenic variants (Ensenauer, 2004). This alteration has also been shown to have diminished thermal stability (Nasser, 2004). The p.A314V alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

IVD-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2024

The IVD c.941C>T variant is predicted to result in the amino acid substitution p.Ala314Val. This variant, which has also been described as 932C>T (A282V) in the literature, has been documented causative for isovaleric acidemia and has been reported to be associated with a more clinically mild phenotype or found in asymptomatic individuals identified by newborn screening (Mohsen et al. 1998. PubMed ID: 9665741; Ensenauer et al. 2004. PubMed ID: 15486829; Vockley and Ensenauer. 2006. PubMed ID: 16602101; Couce et al. 2017. PubMed ID: 27904153). In functional studies, the activity of the IVD enzyme with the p.Ala314Val substitution was reduced to <20% of wild-type (Mohsen et al. 1998. PubMed ID: 9665741). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.34	T
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.014	D;D;T
Vest4		0.80
MVP		0.96
MPC		0.64
ClinPred		0.14	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77

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: rs28940889; hg19: chr15-40707653;