ClinVar Miner

Submissions for variant NM_000143.3(FH):c.437G>A (p.Gly146Glu) (rs11545654)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166128 SCV000216899 likely pathogenic Hereditary cancer-predisposing syndrome 2017-07-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Structural Evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes)
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000345017 SCV000338909 uncertain significance not provided 2016-01-11 criteria provided, single submitter clinical testing
Invitae RCV000635317 SCV000756714 likely pathogenic Fumarase deficiency 2018-12-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 146 of the FH protein (p.Gly146Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals and families affected with hereditary leiomyomatosis and renal cell cancer (Invitae). ClinVar contains an entry for this variant (Variation ID: 186519). 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. 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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