Submissions for variant NM_001243279.3(ACSF3):c.1470G>C (p.Glu490Asp)

gnomAD frequency: 0.00004  dbSNP: rs147538370

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000444454	SCV000511955	uncertain significance	not provided	2021-10-11	criteria provided, single submitter	clinical testing	Observed with a second ACSF3 variant in individuals with CMAMMA, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Levtova et al., 2018); 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: 26827111, 32980267, 29858964)
CeGaT Center for Human Genetics Tuebingen	RCV000444454	SCV001249837	likely pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001245382	SCV001418665	pathogenic	Combined malonic and methylmalonic acidemia	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 490 of the ACSF3 protein (p.Glu490Asp). This variant is present in population databases (rs147538370, gnomAD 0.1%). This missense change has been observed in individuals with ACSF3-related conditions (PMID: 26827111, 30740739). ClinVar contains an entry for this variant (Variation ID: 377432). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACSF3 protein function. For these reasons, this variant has been classified as Pathogenic.
Pars Genome Lab	RCV001245382	SCV001652882	uncertain significance	Combined malonic and methylmalonic acidemia	2021-05-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001245382	SCV001781378	uncertain significance	Combined malonic and methylmalonic acidemia	2021-07-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282137	SCV002572027	uncertain significance	not specified	2023-03-27	criteria provided, single submitter	clinical testing	Variant summary: ACSF3 c.1470G>C (p.Glu490Asp) results in a conservative amino acid change located in the AMP-binding enzyme, C-terminal domain (IPR025110) 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 0.00024 in 251044 control chromosomes (gnomAD). This frequency is not higher than estimated for a pathogenic variant in ACSF3 causing Combined Malonic And Methylmalonic Aciduria (0.00024 vs 0.0058), allowing no conclusion about variant significance. c.1470G>C has been reported in the literature as a homozygous genotype in at-least one individual with elevated methylmalonic acid levels (example, Pupavac_2016) and as a presumed compound heterozygous (phase not specified) in at-least three additional individuals in an unselected cohort with combined malonic and methylmalonic aciduria (CMAMMA) who reported normal levels of MMA (example Levtova_2019). CMAMMA has been reported as a probably benign condition with its expressivity determined by other genetic or environmental factors. 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic, n=1; Likely pathogenic, n=1; VUS, n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV001245382	SCV004210577	uncertain significance	Combined malonic and methylmalonic acidemia	2023-06-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001245382	SCV001457766	uncertain significance	Combined malonic and methylmalonic acidemia	2020-01-07	no assertion criteria provided	clinical testing