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

gnomAD frequency: 0.00071  dbSNP: rs150487794

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185748	SCV000238677	pathogenic	not provided	2024-12-09	criteria provided, single submitter	clinical testing	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: 36717752, 21785126, 29858964, 21841779, 26915364, 34426522, 32944792, 31980526, 34440436, 33879512)
Eurofins Ntd Llc (ga)	RCV000185748	SCV000331886	uncertain significance	not provided	2015-06-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000024132	SCV000771501	pathogenic	Combined malonic and methylmalonic acidemia	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 359 of the ACSF3 protein (p.Glu359Lys). This variant is present in population databases (rs150487794, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with combined malonic and methylmalonic aciduria (PMID: 21785126, 21841779, 26915364, 30740739; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31136). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ACSF3 protein function with a positive predictive value of 95%. 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 acidemia	2022-09-19	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 as a biallelic genotype in multiple individuals affected with Combined Malonic And Methylmalonic Aciduria (CMAMMA) presenting 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 effects of the variant in-vitro. One study showed that cells derived from patients harboring the variant have increased accumulation of MMA in the media, and the expression of wild-type ACSF3 in these cells restores the media MMA to levels similar to controls (e.g. Sloan_2011). Another study demonstrated that cells from a homozygous patient have altered metabolic profiles as determined by Seahorse assays (e.g. Wehbe_2019). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority of submitters classified the variant as either pathogenic (n=3) or likely pathogenic (n=1), and two submitters classified it as VUS. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000024132	SCV001522238	likely pathogenic	Combined malonic and methylmalonic acidemia	2024-03-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000024132	SCV002021285	likely pathogenic	Combined malonic and methylmalonic acidemia	2022-06-08	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000024132	SCV004175671	pathogenic	Combined malonic and methylmalonic acidemia	2022-05-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000185748	SCV004226685	likely pathogenic	not provided	2023-02-07	criteria provided, single submitter	clinical testing	PP1, PP3, PM3_strong
CeGaT Center for Human Genetics Tuebingen	RCV000185748	SCV004701707	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ACSF3: PM3:Very Strong, PM2:Supporting, PP3
Fulgent Genetics, Fulgent Genetics	RCV000024132	SCV005641607	pathogenic	Combined malonic and methylmalonic acidemia	2024-04-30	criteria provided, single submitter	clinical testing
OMIM	RCV000024132	SCV000045423	pathogenic	Combined malonic and methylmalonic acidemia	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
PreventionGenetics, part of Exact Sciences	RCV003415738	SCV004109332	pathogenic	ACSF3-related disorder	2023-11-21	no assertion criteria provided	clinical testing	The ACSF3 c.1075G>A variant is predicted to result in the amino acid substitution p.Glu359Lys. This variant has been reported in both the compound heterozygous and homozygous states in multiple unrelated individuals diagnosed with combined malonic and methylmalonic aciduria (CMAMMA) (Alfares et al. 2011. PubMed ID: 21785126; Sloan et al. 2011. PubMed ID: 21841779; de Sain-van der Velden et al. 2016. PubMed ID: 26915364; Brasil et al. 2018. PubMed ID: 30041674). It has been found to be one of the most commonly reported causative variants in ACSF3 (Levtova et al. 2019. PubMed ID: 30740739). This variant is reported in 0.11% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.