Submissions for variant NM_025136.4(OPA3):c.123C>G (p.Ile41Met)

gnomAD frequency: 0.00001  dbSNP: rs763083098

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001134311	SCV001294046	uncertain significance	Optic atrophy 3	2017-05-01	criteria provided, single submitter	clinical testing	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001134312	SCV001294047	uncertain significance	3-Methylglutaconic aciduria type 3	2017-05-01	criteria provided, single submitter	clinical testing	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.
Pediatric Department, Xiangya Hospital, Central South University	RCV003232217	SCV002760198	uncertain significance	See cases		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002482258	SCV002775326	uncertain significance	3-Methylglutaconic aciduria type 3; Optic atrophy 3	2022-02-23	criteria provided, single submitter	clinical testing
Invitae	RCV002482258	SCV003443260	uncertain significance	3-Methylglutaconic aciduria type 3; Optic atrophy 3	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 41 of the OPA3 protein (p.Ile41Met). This variant is present in population databases (rs763083098, gnomAD 0.09%). This missense change has been observed in individual(s) with clinical features of optic atrophy (PMID: 25205859, 28081242). ClinVar contains an entry for this variant (Variation ID: 894212). 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: "Benign"; Align-GVGD: "Class C0"). 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.
Revvity Omics, Revvity	RCV003132239	SCV003810665	likely pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331048	SCV004038627	likely benign	not specified	2023-08-02	criteria provided, single submitter	clinical testing	Variant summary: c.123C>G (p.Ile41Met) 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 6.8e-05 in 251366 control chromosomes. The observed variant frequency is approximately 108 fold of the estimated maximal expected allele frequency for a pathogenic variant in OPA3 causing Optic Atrophy 3 phenotype (6.3e-07), strongly suggesting that the variant is benign. c.123C>G has been reported in the literature in individuals affected with Optic Atrophy 3 without strong evidence for causality (examples: Chen_2014, Fan_2020, Li_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Optic Atrophy 3. At-least one co-occurrence with another apparently pathogenic variant(s) has been reported (OPA1 c.1682-1G>A) in two individuals likely from one family with suspected optic neuropathy, providing supporting evidence for a benign role (Li_2020). To our knowledge, no occurrence of this variant in individuals affected with autosomal recessive 3-Methylglutaconic Aciduria Type 3 and experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25205859, 32883240, 32855858). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Likely pathogenic: n=1; VUS: n=3). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003393857	SCV004120147	uncertain significance	OPA3-related condition	2023-03-09	criteria provided, single submitter	clinical testing	The OPA3 c.123C>G variant is predicted to result in the amino acid substitution p.Ile41Met. This variant has been reported in the heterozygous state in patients with optic atrophy with or without cataracts (Chen et al 2014. PubMed ID: 25205859; Fan et al. 2020. PubMed ID: 32883240; Li et al. 2020. PubMed ID: 32855858). Inheritance from affected and unaffected parents has been documented and suggests that this variant may be incompletely penetrant (Fan et al. 2020. PubMed ID: 32883240). This variant is reported in 0.082% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-46087900-G-C). This variant has been interpreted by the majority of submitters in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/894212). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.