ClinVar Genomic variation as it relates to human health

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 167 of the IVD protein (p.Met167Val). This variant is present in population databases (rs574434706, gnomAD 0.1%). This missense change has been observed in individual(s) with a positive newborn screening result for IVD-related disease (PMID: 32505769). ClinVar contains an entry for this variant (Variation ID: 855170). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Met167 amino acid residue in IVD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26018748, 27904153, 31707166). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:26018748). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.929>=0.6, 3CNET: 0.938>=0.75). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0001427). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.

Variant summary: IVD c.490A>G (p.Met164Val) results in a 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 0.00014 in 251490 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in IVD causing Isovaleryl-CoA Dehydrogenase Deficiency (0.00014 vs 0.0022), allowing no conclusion about variant significance. c.490A>G has been reported in the literature in at least one compound heterozygous individual affected with Isovaleric acidemia (e.g. Lin_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Isovaleryl-CoA Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32505769). ClinVar contains an entry for this variant (Variation ID: 855170). Based on the evidence outlined above, the variant was classified as uncertain significance.