15-40415454-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
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
Consequence
NM_002225.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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IVD | NM_002225.5 | c.932C>T | p.Ala311Val | missense_variant | Exon 9 of 12 | ENST00000487418.8 | NP_002216.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
IVD | ENST00000487418.8 | c.932C>T | p.Ala311Val | missense_variant | Exon 9 of 12 | 1 | NM_002225.5 | ENSP00000418397.3 |
Frequencies
GnomAD3 genomes AF: 0.000729 AC: 111AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000641 AC: 161AN: 251360Hom.: 0 AF XY: 0.000640 AC XY: 87AN XY: 135866
GnomAD4 exome AF: 0.000919 AC: 1344AN: 1461838Hom.: 0 Cov.: 31 AF XY: 0.000925 AC XY: 673AN XY: 727218
GnomAD4 genome AF: 0.000729 AC: 111AN: 152318Hom.: 0 Cov.: 33 AF XY: 0.000725 AC XY: 54AN XY: 74480
ClinVar
Submissions by phenotype
Isovaleryl-CoA dehydrogenase deficiency Pathogenic:9
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. -
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. -
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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. The following publications have been ascertained in the context of this evaluation (PMID: 27904153, 15486829, 9665741). ClinVar contains an entry for this variant (Variation ID: 100060). Based on the evidence outlined above, the variant was classified as pathogenic. -
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not provided Pathogenic:6
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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 (PMID: 15486829); 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 (PMID: 15486829); Published functional studies demonstrate A314V results in reduced isovaleryl-CoA dehydrogenase activity compared to wild-type (PMID: 9665741); This variant is associated with the following publications: (PMID: 26937393, 16602101, 27904153, 34535384, 25087612, 22995991, 15486829, 15337167, 22960500, 26018748, 31980526, 28631226, 29431110, 31707166, 34426522, 9665741, 33496032, 32977617, 37443404, 32778825) -
IVD: PM3:Strong, PM1, PM2, PP4, PS3:Supporting -
Inborn genetic diseases Pathogenic:1
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 disorder Pathogenic:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at