Submissions for variant NM_003705.5(SLC25A12):c.870G>C (p.Glu290Asp)

gnomAD frequency: 0.00001  dbSNP: rs757002057

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002031879	SCV002310105	uncertain significance	not provided	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with aspartic acid at codon 290 of the SLC25A12 protein (p.Glu290Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs757002057, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with SLC25A12-related conditions. 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 tolerated. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471252	SCV002768878	uncertain significance	Developmental and epileptic encephalopathy, 39	2019-08-28	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_003705.4(SLC25A12):c.870G>C, has been identified in exon 9 of 18 of the SLC25A12 gene. The variant is predicted to result in a minor amino acid change from glutamic acid to aspartic acid at position 290 of the protein (NP_003696.2(SLC25A12):p.(Glu290Asp)). The glutamic acid residue at this position has high conservation (100 vertebrates, UCSC), and is located within the N-terminal domain. In silico predictions of pathogenicity for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.0007% (2 heterozygotes, 0 homozygotes). This variant has not been previously reported in clinical cases. Based on the information available at the time of curation, this variant has been classified as VARIANT of UNCERTAIN SIGNIFICANCE (VUS).