Submissions for variant NM_001191061.2(SLC25A22):c.267C>G (p.Phe89Leu)

gnomAD frequency: 0.00024  dbSNP: rs143064022

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189316	SCV000242951	uncertain significance	not provided	2018-07-09	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SLC25A22 gene. The F89L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 21/23990 (0.09%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, the F89L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Laboratory Services, Illumina	RCV000369722	SCV000374631	uncertain significance	Early myoclonic encephalopathy	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000536650	SCV000634006	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 89 of the SLC25A22 protein (p.Phe89Leu). This variant is present in population databases (rs143064022, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with SLC25A22-related conditions. ClinVar contains an entry for this variant (Variation ID: 207157). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SLC25A22 protein function. 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.
Ambry Genetics	RCV002433856	SCV002744787	uncertain significance	Inborn genetic diseases	2024-01-17	criteria provided, single submitter	clinical testing	The c.267C>G (p.F89L) alteration is located in exon 5 (coding exon 4) of the SLC25A22 gene. This alteration results from a C to G substitution at nucleotide position 267, causing the phenylalanine (F) at amino acid position 89 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.