ClinVar Miner

Submissions for variant NM_001243279.3(ACSF3):c.1411C>T (p.Arg471Trp) (rs138680796)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mayo Clinic Laboratories, Mayo Clinic RCV000024133 SCV000782657 uncertain significance Combined malonic and methylmalonic aciduria 2017-04-26 criteria provided, single submitter clinical testing
Invitae RCV000024133 SCV000952257 uncertain significance Combined malonic and methylmalonic aciduria 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 471 of the ACSF3 protein (p.Arg471Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs138680796, ExAC 0.04%). This variant has been observed in individuals affected with combined malonic and methylmalonic aciduria (PMID: 29858964, 21841779, 21785126). ClinVar contains an entry for this variant (Variation ID: 31137). Experimental studies have shown that this missense change disrupts ACSF3 protein function in vitro (PMID: 9030548). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000024133 SCV001158168 uncertain significance Combined malonic and methylmalonic aciduria 2019-02-15 criteria provided, single submitter clinical testing The ACSF3 c.1411C>T; p.Arg471Trp variant (rs138680796), is reported in the literature in the homozygous state in two individuals affected with combined malonic and methylmalonic aciduria (CMAMMA) (Alfares 2011, Sloan 2011). This variant is found in the Ashkenazi Jewish population with an overall allele frequency of 0.71% (73/10360 alleles) in the Genome Aggregation Database, though at least one affected individual with this variant was of Ashkenazi descent (Alfares 2011). The arginine at codon 471 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Another variant at the same codon (p.Arg471Gln) was also reported in an individual with CMAMMA, though its clinical significance remains uncertain (Sloan 2011). Given the lack of clinical and functional data, the significance of the p.Arg471Trp variant is uncertain at this time. References: Alfares A et al. Combined malonic and methylmalonic aciduria: exome sequencing reveals mutations in the ACSF3 gene in patients with a non-classic phenotype. J Med Genet. 2011 Sep;48(9):602-5. Sloan JL et al. Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria. Nat Genet. 2011 Aug 14;43(9):883-6.
GeneDx RCV001588825 SCV001816402 pathogenic not provided 2021-04-19 criteria provided, single submitter clinical testing Published functional studies of the equivalent residue in E. coli resulted in complete loss of fatty acyl-CoA synthetase enzymatic activity (Black et al., 1997); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); 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: 29858964, 21841779, 9030548, 21785126)
OMIM RCV000024133 SCV000045424 pathogenic Combined malonic and methylmalonic aciduria 2011-08-14 no assertion criteria provided literature only
Natera, Inc. RCV001274022 SCV001457706 uncertain significance Methylmalonic acidemia 2020-09-16 no assertion criteria provided clinical testing

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