Submissions for variant NM_006796.3(AFG3L2):c.98A>C (p.Gln33Pro)

gnomAD frequency: 0.00211  dbSNP: rs777868371

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000312572	SCV000407658	likely benign	Autosomal dominant cerebellar ataxia	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000992838	SCV000519011	likely benign	not provided	2020-07-10	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000992838	SCV001145401	benign	not provided	2019-01-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000992838	SCV002132878	uncertain significance	not provided	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 33 of the AFG3L2 protein (p.Gln33Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with AFG3L2-related conditions. ClinVar contains an entry for this variant (Variation ID: 326114). 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 AFG3L2 protein function with a negative predictive value of 95%. 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	RCV002523035	SCV003668888	likely benign	Inborn genetic diseases	2022-03-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003940294	SCV004761265	likely benign	AFG3L2-related disorder	2021-03-02	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).