ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1154C>A (p.Ala385Asp) (rs727503926)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000153234 SCV000202708 uncertain significance not provided 2014-01-06 criteria provided, single submitter clinical testing
GeneDx RCV000153234 SCV000251430 likely pathogenic not provided 2018-03-06 criteria provided, single submitter clinical testing This variant is denoted FH c.1154C>A at the cDNA level, p.Ala385Asp (A385D) at the protein level, and results in the change of an Alanine to an Aspartic Acid (GCC>GAC). This variant has been reported in at least one individual with skin and uterine leiomyomas (Wei 2006). FH Ala385Asp was not observed in large population cohorts (Lek 2016). This variant is located in the core helix (Picaud 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider FH Ala385Asp to be a likely pathogenic variant.
Ambry Genetics RCV000217529 SCV000276015 pathogenic Hereditary cancer-predisposing syndrome 2019-11-01 criteria provided, single submitter clinical testing The p.A385D pathogenic mutation (also known as c.1154C>A), located in coding exon 8 of the FH gene, results from a C to A substitution at nucleotide position 1154. The alanine at codon 385 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration has been identified in at least two families with multiple cutaneous and uterine leiomyomas and diagnosis of hereditary leiomyomatosis and renal cell carcinoma (HLRCC) (Wei MH et al. J. Med. Genet. 2006 Jan; 43(1):18-27; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000445620 SCV000537261 uncertain significance Hereditary leiomyomatosis and renal cell cancer 2017-01-17 criteria provided, single submitter clinical testing
Invitae RCV001058206 SCV001222759 likely pathogenic Fumarase deficiency 2020-01-07 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 385 of the FH protein (p.Ala385Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hereditary leiomyomatosis and renal cell cancer (PMID: 15937070, Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1025C>A, p.Ala342Asp in the literature. ClinVar contains an entry for this variant (Variation ID: 167065). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). 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. 5

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