ClinVar Miner

Submissions for variant NM_000144.5(FXN):c.389G>T (p.Gly130Val)

gnomAD frequency: 0.00004  dbSNP: rs104894107
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000992016 SCV001143968 pathogenic not provided 2022-11-18 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 segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 11030757, 18537827) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Genetic Services Laboratory, University of Chicago RCV000992016 SCV002064373 likely pathogenic not provided 2018-09-10 criteria provided, single submitter clinical testing DNA sequence analysis of the FXN gene demonstrated a sequence change, c.389G>T, in exon 4 that results in an amino acid change, p.Gly130Val. The p.Gly130Val change affects a highly conserved amino acid residue located in a domain of the FXN protein that is known to be functional. The p.Gly130Val substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). PMID: 9150176 identified this sequence change in the compound heterozygous state with a GAA trinucleotide repeat expansion in three siblings with atypical Friedreich ataxia phenotype. PMID: 17331979 showed that this sequence change interfered with FXN protein expression in transfected HEK293T cells. This sequence change has been described in the genome Aggregation Database (gnomAD) with a very low population frequency of 0.0063% (dbSNP rs104894107).
AiLife Diagnostics, AiLife Diagnostics RCV000992016 SCV002501403 uncertain significance not provided 2021-05-26 criteria provided, single submitter clinical testing
GeneDx RCV000992016 SCV005327016 pathogenic not provided 2024-03-21 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect with this variant resulting in a protein with a defect in protein processing (PMID: 28812047); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9700204, 11020385, 17331979, 9989622, 26704351, 11030757, 20162437, 26301374, 9150176, 11843702, 26339677, 21298097, 19629184, 19494730, 18537827, 12019217, 10543403, 31980526, 28812047)
OMIM RCV000004189 SCV000024355 pathogenic Friedreich ataxia 2007-04-15 no assertion criteria provided literature only

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