ClinVar Miner

Submissions for variant NM_000143.3(FH):c.923C>G (p.Ala308Gly) (rs1057524385)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000430394 SCV000535402 likely pathogenic not provided 2017-01-17 criteria provided, single submitter clinical testing The A308G variant in the FH gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A308G variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A308G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (L303S, N310Y, F312C, F312S) have been reported in the Human Gene Mutation Database in association with FH deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. The A308G variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000555247 SCV000632496 likely pathogenic Fumarase deficiency 2018-01-04 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 308 of the FH protein (p.Ala308Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. This variant is not present in population databases (ExAC no frequency). A different laboratory has reported this variant on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with fumarate deficiency (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 392178). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change that has been reported in an individual with a diagnosis of fumarate deficiency. This indicates that the variant is pathogenic but additional evidence is necessary to prove that conclusively. For these reasons, this variant has been classified as a Likely Pathogenic.

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