ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1020T>A (p.Asn340Lys) (rs398123159)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220396 SCV000275280 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000445596 SCV000537251 pathogenic Multiple cutaneous leiomyomas 2017-01-17 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078140 SCV000109978 likely pathogenic not provided 2018-08-19 criteria provided, single submitter clinical testing
GeneDx RCV000078140 SCV000251426 likely pathogenic not provided 2018-07-03 criteria provided, single submitter clinical testing This variant is denoted FH c.1020T>A at the cDNA level, p.Asn340Lys (N340K) at the protein level, and results in the change of an Asparagine to a Lysine (AAT>AAA). This variant, also defined as FH Asn297Lys using alternate nomenclature, has been reported in at least one individual with cutaneous and uterine leiomyomas and in at least one individual with early-onset metastatic papillary renal cell carcinoma (Wei 2006, Chen 2014, Kopp 2017). FH Asn340Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider FH Asn340Lys to be a likely pathogenic variant.
Invitae RCV000228017 SCV000283659 pathogenic Fumarase deficiency 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 340 of the FH protein (p.Asn340Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs398123159, ExAC 0.001%). This variant has been reported in multiple individuals and families affected with hereditary leiomyomatosis and renal cell cancer (HLRCC), and has been observed to segregate with disease (PMID: 15937070, 12772087, 26457356, Invitae). This variant is also known as 891T>A (N297K, N297D) in the literature. ClinVar contains an entry for this variant (Variation ID: 92447). An analysis of the FH protein crystal structure revealed that the Asn340 residue is semi-conserved and localizes in the core helices. A variant affecting this residue is predicted to affect inter- or intrasubunit interactions, thereby disrupting protein function (PMID: 21445611). For these reasons, this variant has been classified as Pathogenic.

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