ClinVar Genomic variation as it relates to human health

Variant summary: ACO2 c.220C>G (p.Leu74Val) results in a conservative amino acid change located in the Aconitase/3-isopropylmalate dehydratase large subunit, alpha/beta/alpha domain (IPR001030) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0037 in 250844 control chromosomes in the gnomAD database, including 4 homozygotes. c.220C>G has been reported in the literature in individuals affected with isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy (Metodiev_2014, Benkirane_2021, Charif_2021). These reports do not provide unequivocal conclusions about association of the variant with ACO2-Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function and this variant was unable to complement the growth defect in yeast model (Metodiev_2014). The following publications have been ascertained in the context of this evaluation (PMID: 34234304, 34056600, 25351951). ClinVar contains an entry for this variant (Variation ID: 189310). Based on the evidence outlined above, the variant was classified as likely benign.

Functional data demonstrated that the mutant protein failed to rescue mitochondrial aconitase deficient yeast strain (PMID: 25351951); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28463998, 29577077, 34056600, 31106992, 30689204, 31765440, 32519519, 34426522, 34354088, 34234304, 25351951, 32449285, 30831606, 30118607, 38007539, 37734845)

ACO2: BS2

The ACO2 p.Leu74Val variant was identified in the literature in two adult male siblings with optic atrophy beginning in childhood; the p.L74V variant was found as a compound heterozygous mutation with a ACO2 p.G661R variant. Decreased ACO2 protein levels were observed in fibroblasts from these two patients (Metodiev_2014_PMID:25351951). The variant was identified in dbSNP (ID: rs141772938) and ClinVar (classified as uncertain significance by Fulgent Genetics, GeneDx, EGL Genetics and Mayo Clinic, and as likely pathogenic by CeGaT Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 1055 of 282256 chromosomes (4 homozygous) at a frequency of 0.003738 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 839 of 128790 chromosomes (freq: 0.006514), Other in 30 of 7208 chromosomes (freq: 0.004162), European (Finnish) in 80 of 25082 chromosomes (freq: 0.00319), South Asian in 52 of 30602 chromosomes (freq: 0.001699), African in 23 of 24894 chromosomes (freq: 0.000924) and Latino in 31 of 35394 chromosomes (freq: 0.000876), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Leu74 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

The ACO2 c.220C>G variant is predicted to result in the amino acid substitution p.Leu74Val. This variant has been reported several times in the compound heterozygous state in individuals affected with optic atrophy and has been found to segregate with disease in the cases of multiple affected family members (Metodiev et al. 2014. PubMed ID: 25351951; Kelman et al. 2018. PubMed ID: 30118607; Benkirane et al. 2021. PubMed ID: 34234304; Charif et al. 2021. PubMed ID: 34056600). In many of the reported cases, this variant was found in combination with a loss-of-function variant suggesting the p.Leu74Val substitution has a mild effect on the encoded protein (Charif et al. 2021. PubMed ID: 34056600). Functional studies suggest that this variant may alter stability of the protein (Metodiev et al. 2014. PubMed ID: 25351951). However, this variant has also been reported at frequencies up to ~0.7%, including four homozygotes in a large population database. This variant also has conflicting interpretations of pathogenicity in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/189310/). Currently, we suspect that this variant is pathogenic and represents a mildly hypomorphic allele; however, at this time, the clinical significance of this variant is uncertain due to the conflicting functional and genetic evidence.

Variant identified in multiple GenomeConnect participants. Variant classified, most recently, as Uncertain significance and reported on 01-02-2020 by Lab or GTR ID 26957. Variant previously reported as a "disease-causing mutation" by GTR ID 26957 in April 2015. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.