Submissions for variant NM_006796.3(AFG3L2):c.2167G>A (p.Val723Met)

gnomAD frequency: 0.00024  dbSNP: rs139469785

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000195592	SCV000251092	uncertain significance	not provided	2021-06-15	criteria provided, single submitter	clinical testing	Identified with a likely pathogenic variant on the opposite allele (in trans) in a patient with spinocerebellar ataxia 28 in published literature; however, paternal testing was not completed (Tunc et al., 2019); Identified as heterozygous in an individual with growth delay, retinal dystrophy, sensorineural deafness, myopathy, ataxia, and combined pituitary hormone deficiency who was also homozygous for a variant in OTX2 which was expected to explain his phenotype (Catania et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31111429, 30773800, 32237276, 27535533, 33564152, 33841295, 31589614)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195592	SCV001040606	pathogenic	not provided	2024-06-26	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 723 of the AFG3L2 protein (p.Val723Met). This variant is present in population databases (rs139469785, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive spinocerebellar ataxia (PMID: 31111429, 34333379, 34418069, 34445196). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 214062). 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 AFG3L2 protein function. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000195592	SCV001145394	likely pathogenic	not provided	2024-06-27	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with autosomal recessive spastic ataxia. Recent data suggests heterozygous carriers of a recessive AFG3L2 variant may exhibit mild or subclinical symptoms and older age of onset. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein. The variant is located in a region that is considered important for protein function and/or structure.
Illumina Laboratory Services, Illumina	RCV001122821	SCV001281589	uncertain significance	Spinocerebellar ataxia type 28	2018-01-15	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.
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV001640293	SCV001519092	pathogenic	Spastic ataxia 5	2021-01-04	criteria provided, single submitter	research
Ambry Genetics	RCV002517193	SCV003690598	uncertain significance	Inborn genetic diseases	2021-02-22	criteria provided, single submitter	clinical testing	The c.2167G>A (p.V723M) alteration is located in exon 16 (coding exon 16) of the AFG3L2 gene. This alteration results from a G to A substitution at nucleotide position 2167, causing the valine (V) at amino acid position 723 to be replaced by a methionine (M). The p.V723M alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224221	SCV003919826	uncertain significance	Spinocerebellar ataxia type 28; Spastic ataxia 5; Optic atrophy 12	2021-03-30	criteria provided, single submitter	clinical testing	AFG3L2 NM_006796.2 exon 16 p.Val723Met (c.2167G>A): This variant has not been reported in the literature and is present in 0.02% (32/129162) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/18-12337348-C-T). This variant is present in ClinVar (Variation ID:214062). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV000195592	SCV005431785	uncertain significance	not provided	2024-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001640293	SCV005884515	likely pathogenic	Spastic ataxia 5	2024-12-24	criteria provided, single submitter	clinical testing	Variant summary: AFG3L2 c.2167G>A (p.Val723Met) results in a conservative amino acid change located in the Peptidase M41 domain (IPR000642) 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 0.00017 in 251448 control chromosomes (gnomAD). This frequency is not higher than the maximum estimated for a pathogenic variant in AFG3L2 causing Spastic Ataxia 5, Autosomal Recessive, allowing no conclusion about variant significance. The variant, c.2167G>A, has been reported in the literature in multiple compound heterozygous individuals affected with spastic ataxia and spinocerebellar ataxia (e.g. Tunc_2019, Chiang_2021, Sainio_2021); and in at least one family segregation with the disease phenotype was reported. The variant was also reported in heterozygous state in individual(s) affected with optic neuropathy (Charif_2021), however no supportive evidence was provided for causality. At least one publication reported experimental evidence, and demonstrated mitochondrial alterations fibroblasts derived from a compound heterozygous patient (Tunc_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31111429, 33841295, 34333379, 34418069). ClinVar contains an entry for this variant (Variation ID: 214062). While this variant has been reported in the literature, the clinical significance of the variant for Optic Atrophy 12 could not be established. Based on the evidence outlined above, this variant is likely pathogenic for Spastic Ataxia 5, Autosomal Recessive.