ClinVar Miner

Submissions for variant NM_174917.5(ACSF3):c.1672C>T (p.Arg558Trp) (rs141090143)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000185751 SCV000780547 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000185751 SCV000281319 pathogenic not provided 2014-11-10 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000185751 SCV000854934 pathogenic not provided 2018-08-14 criteria provided, single submitter clinical testing
GeneDx RCV000185751 SCV000238680 pathogenic not provided 2017-02-23 criteria provided, single submitter clinical testing The R558W missense variant in the ACSF3 gene has been reported previously in association with combined malonic and methylmalonic aciduria (CMAMMA) and was identified on 5 of 18 alleles in 9 patients with CMAMMA (Sloan et al., 2011). We interpret R558W as a pathogenic variant.
Invitae RCV000024130 SCV000771502 pathogenic Combined malonic and methylmalonic aciduria 2019-01-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 558 of the ACSF3 protein (p.Arg558Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs141090143, ExAC 0.4%). This variant has been reported as homozygous or in combination with another ACSF3 variant in several individuals affected with methylmalonic acidemia (PMID: 21841779, 26827111, Invitae) and it has been observed on the opposite chromosome (in trans) from other pathogenic variants in some of these individuals. This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 31134). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000024130 SCV000711714 likely pathogenic Combined malonic and methylmalonic aciduria 2016-08-25 criteria provided, single submitter clinical testing The p.Arg558Trp variant in ACSF3 has been reported in 1 homozygous and 5 compoun d heterozygous individuals with clinical features of combined malonic and methyl malonic aciduria and 1 compound heterozygous individual with elevated methyl mal onic acid levels (Sloan 2011, Pupavac 2016). At least one patient responded to c obalamin treatment (Pupavac 2016). This variant has also been reported in ClinVa r (Variation ID#31134). In addition, this variant has been identified in 0.45% ( 278/62114) of European chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs141090143). Although the frequency is appr eciable, there is a statistically significantly higher frequency in cases compar ed to the general population in ExAC (p<0.0001). Computational prediction tools and conservation analysis suggest that the p.Arg558Trp variant may impact the pr otein, though this information is not predictive enough to determine pathogenici ty. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg558Trp variant is likely pathogenic.
OMIM RCV000024130 SCV000045421 pathogenic Combined malonic and methylmalonic aciduria 2011-08-14 no assertion criteria provided literature only

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