ClinVar Miner

Submissions for variant NM_000143.3(FH):c.703C>T (p.His235Tyr) (rs863223968)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199454 SCV000251420 likely pathogenic not provided 2016-09-28 criteria provided, single submitter clinical testing The H235Y variant in the FH gene has previously been reported to segregate with disease in at least one family with hereditary leiomyomatosis and renal cell cancer (HLRCC) (Kamai et al., 2012). The H235Y variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H235Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same residue (H235R, H235D), as well as variants in nearby residues (K230R, R233C, R233L, R233H) have been reported in the Human Gene Mutation Database in association with FH-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on currently available evidence, H235Y is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded.

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