ClinVar Miner

Submissions for variant NM_001243279.3(ACSF3):c.1081G>A (p.Gly361Ser)

gnomAD frequency: 0.00009  dbSNP: rs145285434
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000649671 SCV000771500 uncertain significance Combined malonic and methylmalonic acidemia 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 361 of the ACSF3 protein (p.Gly361Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs145285434, ExAC 0.01%). This variant has been observed in combination with another ACSF3 variant in an individual affected with combined malonic and methylmalonic aciduria (PMID: 29858964). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000649671 SCV000784426 uncertain significance Combined malonic and methylmalonic acidemia 2018-03-05 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001093042 SCV001249836 likely pathogenic not provided 2022-02-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000649671 SCV001737180 uncertain significance Combined malonic and methylmalonic acidemia 2021-05-18 criteria provided, single submitter clinical testing
GeneDx RCV001093042 SCV001755833 uncertain significance not provided 2020-12-02 criteria provided, single submitter clinical testing Identified in a patient with combined malonic and methylmalonic aciduria in the presence of a second ACSF3 variant in published literature (Levtova et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30740739)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002307575 SCV002600611 uncertain significance not specified 2023-12-07 criteria provided, single submitter clinical testing Variant summary: ACSF3 c.1081G>A (p.Gly361Ser) results in a non-conservative amino acid change located in the AMP-dependent synthetase/ligase (IPR000873) of the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250644 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACSF3 causing Combined Malonic And Methylmalonic Aciduria (0.0001 vs 0.0058), allowing no conclusion about variant significance. c.1081G>A has been reported in the literature in an individual affected with Combined Malonic And Methylmalonic Aciduria (Levtova_2019) without evidence of causality. 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: 30740739). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=5) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics RCV000649671 SCV004211510 likely pathogenic Combined malonic and methylmalonic acidemia 2024-03-27 criteria provided, single submitter clinical testing
Natera, Inc. RCV000649671 SCV002092423 uncertain significance Combined malonic and methylmalonic acidemia 2020-01-24 no assertion criteria provided clinical testing

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