ClinVar Miner

Submissions for variant NM_000143.3(FH):c.689A>G (p.Lys230Arg) (rs752232718)

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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 RCV000494410 SCV000581649 pathogenic Hereditary cancer-predisposing syndrome 2019-01-23 criteria provided, single submitter clinical testing 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;Other strong data supporting pathogenic classification
Invitae RCV000534273 SCV000632483 likely pathogenic Fumarase deficiency 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 230 of the FH protein (p.Lys230Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs752232718, ExAC 0.001%). This variant has been reported in several individuals and families affected with multiple cutaneous or uterine leiomyomas (PMID: 11865300, 12761039, 12772087, 26574848). It has also been reported as homozygous in an infant affected with fumarase deficiency (PMID: 9635293). This variant is also known as Lys187Arg in the literature. Experimental studies have shown that this missense change results in reduced fumarate hydratase enzyme activity in both yeast-based assays and cells derived from affected individuals (PMID: 9635293, 11865300, 16206287, 19470762). In summary, this variant is a rare missense change that disrupts protein function in vitro and in vivo, and has been reported in several affected individuals. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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