ClinVar Genomic variation as it relates to human health

The R414Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R414Q variant is observed in 1/11578 (0.01%) alleles from individuals of Latino background, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R414Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. R414 is an important residue for stability and activity of the isovaleryl-CoA dehydrogenase enzyme, and a different missense change at this position (R414L) has been reported, using alternate nomenclature, to be associated with 7% of wild-type enzyme activity when expressed in E. coli (Mohsen et al. 1998). Furthermore, in silico analysis predicts that the R414Q variant is probably damaging to the protein structure/function. In summary, we interpret the R414Q variant as likely pathogenic; however, the possibility that it is benign cannot be excluded.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

The missense variant p.R411Q in IVD (NM_002225.5) has been submitted to ClinVar as Pathogenic/Uncertain Significance. The variant has not been reported in literature in affected indiviudals. The p.R411Q variant is observed in 12/10,080 (0.119%) alleles from individuals of Ashkenazi Jewish background in gnomAD Exomes and in 1/978 (0.1022%) alleles from individuals of South Asian background in 1000 Genomes. The p.R411Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 411 of IVD is conserved in all mammalian species. The nucleotide c.1232 in IVD is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

Variant summary: IVD c.1232G>A (p.Arg411Gln) results in a conservative amino acid change in the last exon of 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 6.4e-05 in 251482 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in IVD causing Isovaleryl-CoA Dehydrogenase Deficiency (6.4e-05 vs 0.0022), allowing no conclusion about variant significance. c.1232G>A, also known as c.1241G>A, has been reported in a heterozygous pediatric individual affected with Isovaleryl-CoA Dehydrogenase Deficiency without long term complications (example: Molema_2018). Two other variations affecting the same amino acid are associated with Isovaleric acidaemia in HGMD (p.R411L and p.411W), suggesting that this is a critical amino acid in the protein. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic.

The IVD c.1241G>A variant is predicted to result in the amino acid substitution p.Arg414Gln. This variant was reported in the homozygous state in an Ashkenazi Jewish individual with isovaleric acidemia who was identified based on abnormal newborn screen results (described as c.1232G>A, p.Arg411Gln in D'Annibale et al. 2021. PubMed ID: 34535384 text and Supplemental Table 1). Activity of the isovaleryl-CoA dehydrogenase enzyme was significantly reduced in patient fibroblasts, and was absent in an expression study using HEK293T cells (D'Annibale et al. 2021. PubMed ID: 34535384). Different substitutions impacting the same amino acid (p.Arg414Leu, p.Arg414Trp) have been reported in individuals with isovaleric acidemia (p.Arg414Leu described as G1232A (Arg382Leu) in Mohsen et al. 1998. PubMed ID: 9665741; p.Arg414Trp described as c.1231C>T, p.Arg382Trp in Ozgul et al. 2014. PubMed ID: 25220015). This variant is reported in 0.12% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-40710422-G-A). Based on the collective evidence, this variant is interpreted as likely pathogenic.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 414 of the IVD protein (p.Arg414Gln). This variant is present in population databases (rs143348838, gnomAD 0.1%). This missense change has been observed in individual(s) with isovaleric acidemia (PMID: 30159853, 34535384; Invitae). This variant is also known as c.1232G>A, p.R411Q. ClinVar contains an entry for this variant (Variation ID: 450659). 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: 34535384). This variant disrupts the p.Arg414 amino acid residue in IVD. Other variant(s) that disrupt this residue have been observed in individuals with IVD-related conditions (PMID: 9665741, 25220015; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.