ClinVar Miner

Submissions for variant NM_001243279.3(ACSF3):c.28C>T (p.Arg10Trp)

gnomAD frequency: 0.00016  dbSNP: rs202182978
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000224144 SCV000280621 likely pathogenic not provided 2014-11-10 criteria provided, single submitter clinical testing
Invitae RCV002516959 SCV003265285 uncertain significance Combined malonic and methylmalonic acidemia 2022-07-12 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 10 of the ACSF3 protein (p.Arg10Trp). This variant is present in population databases (rs202182978, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ACSF3-related conditions. ClinVar contains an entry for this variant (Variation ID: 203604). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 RCV002516959 SCV003822514 uncertain significance Combined malonic and methylmalonic acidemia 2020-04-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003235109 SCV003934236 uncertain significance not specified 2023-05-05 criteria provided, single submitter clinical testing Variant summary: ACSF3 c.28C>T (p.Arg10Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 233810 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACSF3 causing Combined Malonic And Methylmalonic Aciduria (0.00022 vs 0.0058), allowing no conclusion about variant significance. c.28C>T has been reported in the literature in one individual affected with Congenital diaphragmatic hernia (Qiao_2021). This report does not provide unequivocal conclusions about association of the variant with Combined Malonic And Methylmalonic Aciduria. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 34547244). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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