ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1023T>G (p.Asp341Glu) (rs863223973)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000493972 SCV000581631 likely pathogenic Hereditary cancer-predisposing syndrome 2014-09-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000818182 SCV000958781 likely pathogenic Fumarase deficiency 2018-08-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 341 of the FH protein (p.Asp341Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals and families with features consistent with hereditary leiomyomatosis and renal cell cancer (HLRCC) (Invitae, External communication). ClinVar contains an entry for this variant (Variation ID: 214382). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Variants that disrupt the p.Asp341 amino acid residue in FH have been observed in affected individuals (PMID: 21304509, 22528940, 24684806, 21051878). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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