ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1093A>G (p.Ser365Gly) (rs863223966)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220270 SCV000278463 likely pathogenic Hereditary cancer-predisposing syndrome 2016-12-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),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
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000445606 SCV000537257 pathogenic Multiple cutaneous leiomyomas 2017-01-17 criteria provided, single submitter clinical testing
GeneDx RCV000196179 SCV000251416 pathogenic not provided 2018-01-11 criteria provided, single submitter clinical testing This variant is denoted FH c.1093A>G at the cDNA level, p.Ser365Gly (S365G) at the protein level, and results in the change of a Serine to a Glycine (AGC>GGC). This variant, also known as FH Ser322Gly using alternative nomenclature, has been reported in multiple individuals with multiple cutaneous leiomyomas, uterine leiomyomas, and/or renal cancer (Toro 2003, Wei 2006, Arora 2012, Mitchum 2012, Muller 2017). FH Ser365Gly was not observed in large population cohorts (Lek 2016). FH Ser365Gly is located in the active site of the enzyme (Picaud 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000699219 SCV000827920 pathogenic Fumarase deficiency 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 365 of the FH protein (p.Ser365Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) (PMID: 12772087, 22565324, 22243733, Invitae). This variant is also known as A964G (S322G) in the literature. ClinVar contains an entry for this variant (Variation ID: 214374). 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. For these reasons, this variant has been classified as Pathogenic.

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