ClinVar Miner

Submissions for variant NM_001098.3(ACO2):c.220C>G (p.Leu74Val)

gnomAD frequency: 0.00383  dbSNP: rs141772938
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000676884 SCV000251043 likely pathogenic not provided 2024-08-16 criteria provided, single submitter clinical testing 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)
Eurofins Ntd Llc (ga) RCV000676884 SCV000701819 uncertain significance not provided 2016-10-12 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000676884 SCV000892333 likely benign not provided 2023-11-01 criteria provided, single submitter clinical testing ACO2: BP5, BS2
Fulgent Genetics, Fulgent Genetics RCV000764399 SCV000895453 uncertain significance Infantile cerebellar-retinal degeneration; Optic atrophy 9 2018-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000676884 SCV001025827 benign not provided 2024-01-29 criteria provided, single submitter clinical testing
Mendelics RCV000990458 SCV001141450 likely benign Infantile cerebellar-retinal degeneration 2019-05-28 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000169730 SCV002580898 uncertain significance Optic atrophy 9 2022-06-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003987393 SCV004803784 likely benign not specified 2024-01-26 criteria provided, single submitter clinical testing 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.
OMIM RCV002292437 SCV000221272 pathogenic OPTIC ATROPHY 9, AUTOSOMAL RECESSIVE 2014-12-01 no assertion criteria provided literature only
Mayo Clinic Laboratories, Mayo Clinic RCV000676884 SCV000802698 uncertain significance not provided 2016-02-26 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000764399 SCV001423238 not provided Infantile cerebellar-retinal degeneration; Optic atrophy 9 no assertion provided phenotyping only 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000676884 SCV001480164 likely pathogenic not provided 2021-02-01 flagged submission clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000676884 SCV001553452 uncertain significance not provided no assertion criteria provided clinical testing 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.
PreventionGenetics, part of Exact Sciences RCV004535151 SCV004736215 uncertain significance ACO2-related disorder 2023-11-29 no assertion criteria provided clinical testing 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.

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