Submissions for variant NM_001243279.3(ACSF3):c.1301G>C (p.Arg434Pro)

dbSNP: rs137995833

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486667	SCV000568177	uncertain significance	not provided	2018-04-13	criteria provided, single submitter	clinical testing	The R434P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R434P variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R434P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV001274046	SCV003273057	uncertain significance	Combined malonic and methylmalonic acidemia	2022-06-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 434 of the ACSF3 protein (p.Arg434Pro). This variant is present in population databases (rs137995833, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ACSF3-related conditions. ClinVar contains an entry for this variant (Variation ID: 419949). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Revvity Omics, Revvity	RCV001274046	SCV003822512	uncertain significance	Combined malonic and methylmalonic acidemia	2019-06-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003401529	SCV004120055	uncertain significance	ACSF3-related condition	2023-01-11	criteria provided, single submitter	clinical testing	The ACSF3 c.1301G>C variant is predicted to result in the amino acid substitution p.Arg434Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.084% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-89199605-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV001274046	SCV001457762	uncertain significance	Combined malonic and methylmalonic acidemia	2020-06-03	no assertion criteria provided	clinical testing