ClinVar Miner

Submissions for variant NM_001243279.3(ACSF3):c.1075G>A (p.Glu359Lys) (rs150487794)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185748 SCV000238677 pathogenic not provided 2017-03-21 criteria provided, single submitter clinical testing This variant is denoted p.Glu359Lys at the protein level, c.1075 G>A at the cDNA level, and results in the replacement of a Glutamic acid with a Lysine (GAG>AAG) in exon 6 of the ACSF3 gene (NM_174917.3). Mutations in the ACSF3 gene are associated with the autosomal recessive disorder combined malonic and methylmalonic aciduria (CMAMMA).The E359K missense mutation in the ACSF3 gene has been reported previously in association with combined malonic and methylmalonic aciduria (CMAMMA) (Alfares et al., 2011). The variant is found in MMA-MET panel(s).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000185748 SCV000331886 uncertain significance not provided 2015-06-10 criteria provided, single submitter clinical testing
Invitae RCV000024132 SCV000771501 pathogenic Combined malonic and methylmalonic aciduria 2020-10-31 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 359 of the ACSF3 protein (p.Glu359Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs150487794, ExAC 0.1%). This variant has been observed in individuals and families affected with combined malonic and methylmalonic aciduria and to segregate with disease (PMID: 21785126, 26915364, 29858964, 21841779, Invitae). ClinVar contains an entry for this variant (Variation ID: 31136). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000024132 SCV001467827 pathogenic Combined malonic and methylmalonic aciduria 2020-12-11 criteria provided, single submitter clinical testing Variant summary: ACSF3 c.1075G>A (p.Glu359Lys) results in a conservative amino acid change located in the AMP-dependent synthetase/ligase domain (IPR000873) of 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 0.00067 in 250734 control chromosomes (gnomAD). c.1075G>A has been reported in the literature in multiple individuals affected with Combined Malonic And Methylmalonic Aciduria(CMAMMA), both in homozygous and compound heterozygous individuals with elevated levels of MA and/or MMA in urine and/or plasma samples (e.g. Alfares_2011, Sloan_2011, Brasil_2018, Levtova_2019) . These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating the variant's effects in-vitro. One study reports that cells from patients with the variant have increased accumulation of MMA in the media, and that expression of wild-type ACSF3 in these cells restores the media MMA to levels similar to controls (e.g. Sloan_2011). Another study reports that patient cells homozygous for the mutation have altered metabolic profiles as assessed by Seahorse assays (e.g. Wehbe_2019). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as pathogenic (n=2) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000024132 SCV001522238 uncertain significance Combined malonic and methylmalonic aciduria 2019-09-30 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
OMIM RCV000024132 SCV000045423 pathogenic Combined malonic and methylmalonic aciduria 2011-08-14 no assertion criteria provided literature only
Natera, Inc. RCV001274019 SCV001457701 pathogenic Methylmalonic acidemia 2020-09-16 no assertion criteria provided clinical testing

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