ClinVar Miner

Submissions for variant NM_001098.3(ACO2):c.220C>G (p.Leu74Val) (rs141772938)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000676884 SCV000251043 uncertain significance not provided 2018-10-10 criteria provided, single submitter clinical testing The L74V variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The L74Vvariant was observed at a frequency of 0.5%, 47/8598 alleles, in individuals of European ancestry by theNHLBI Exome Sequencing Project, with the reported genotypes indicating that all individuals wereheterozygous for this variant. The L74V variant was also observed in 2/196 alleles from individuals ofItalian ancestry and in 2/178 alleles in individuals of British ancestry by the 1000 Genomes Project (Kerseyet al., 2010). The L74V variant is a conservative amino acid substitution, which is not likely to impactsecondary protein structure as these residues share similar properties. This substitution occurs at a positionthat is conserved across species. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. Therefore, based on the currently available information, it is unclear whether this variantis a pathogenic or a rare benign variant
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000676884 SCV000701819 uncertain significance not provided 2016-10-12 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000676884 SCV000892333 uncertain significance not provided 2020-12-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764399 SCV000895453 uncertain significance Infantile cerebellar-retinal degeneration; Optic atrophy 9 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000676884 SCV001025827 benign not provided 2020-11-25 criteria provided, single submitter clinical testing
Mendelics RCV000990458 SCV001141450 likely benign Infantile cerebellar-retinal degeneration 2019-05-28 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000676884 SCV001480164 likely pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
OMIM RCV000169730 SCV000221272 pathogenic Optic atrophy 9 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 RCV000676884 SCV001423238 not provided not provided no assertion provided phenotyping only Variant interpretted as Pathogenic and reported on 04-21-2015 by Lab or GTR ID 26957. 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.
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.

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