ClinVar Miner

Submissions for variant NM_001243279.3(ACSF3):c.728C>T (p.Pro243Leu)

gnomAD frequency: 0.00022  dbSNP: rs140986055
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000024136 SCV003305294 uncertain significance Combined malonic and methylmalonic acidemia 2021-10-19 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 243 of the ACSF3 protein (p.Pro243Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs140986055, ExAC 0.1%). This missense change has been observed in individual(s) with combined malonic and methylmalonic aciduria (PMID: 21841779). ClinVar contains an entry for this variant (Variation ID: 31140). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003114202 SCV003801298 uncertain significance not specified 2023-01-25 criteria provided, single submitter clinical testing Variant summary: ACSF3 c.728C>T (p.Pro243Leu) results in a non-conservative amino acid change located in the AMP-dependent synthetase/ligase domain (IPR000873) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251160 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACSF3 causing Combined Malonic And Methylmalonic Aciduria (6.8e-05 vs 0.0058), allowing no conclusion about variant significance. c.728C>T has been reported in the literature as a homozygous genotype in at-least one individual affected with biochemical features Combined Malonic And Methylmalonic Aciduria (example, PMID: 30740739, 21841779). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
OMIM RCV000024136 SCV000045427 pathogenic Combined malonic and methylmalonic acidemia 2011-08-14 no assertion criteria provided literature only

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