ClinVar Miner

Submissions for variant NM_138773.4(SLC25A46):c.746G>A (p.Gly249Asp)

gnomAD frequency: 0.00003  dbSNP: rs200725073
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000412631 SCV001231156 uncertain significance Neuropathy, hereditary motor and sensory, type 6B 2024-11-03 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 249 of the SLC25A46 protein (p.Gly249Asp). This variant is present in population databases (rs200725073, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of SLC25A46-related conditions and/or optic atrophy and axonal peripheral neuropathy (PMID: 26168012, 33841295). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372238). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SLC25A46 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect SLC25A46 function (PMID: 27543974). 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 RCV002392936 SCV002671346 uncertain significance Inborn genetic diseases 2022-12-08 criteria provided, single submitter clinical testing The c.746G>A (p.G249D) alteration is located in exon 8 (coding exon 8) of the SLC25A46 gene. This alteration results from a G to A substitution at nucleotide position 746, causing the glycine (G) at amino acid position 249 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
OMIM RCV000412631 SCV000490313 pathogenic Neuropathy, hereditary motor and sensory, type 6B 2017-01-14 no assertion criteria provided literature only

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