ClinVar Miner

Submissions for variant NM_000143.3(FH):c.320A>C (p.Asn107Thr) (rs121913121)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Academic Department of Medical Genetics, University of Cambridge RCV000493777 SCV000992191 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Ambry Genetics RCV000493777 SCV000581634 pathogenic Hereditary cancer-predisposing syndrome 2017-07-14 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,Rarity in general population databases (dbsnp, esp, 1000 genomes),Good segregation with disease (lod 1.5-3 = 5-9 meioses),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000017620 SCV000537226 pathogenic Multiple cutaneous leiomyomas 2017-01-17 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078148 SCV000331122 pathogenic not provided 2015-10-12 criteria provided, single submitter clinical testing
GeneDx RCV000078148 SCV000251443 pathogenic not provided 2018-10-19 criteria provided, single submitter clinical testing The N107T missense variant in the FH gene has been reported in patients diagnosed with leiomyomatosis, including both cutaneous and uterine leiomyomata (for examples, see Tomlinson et al., 2002; Alam et al., 2005; Udager et al., 2014). This variant has been shown to segregate with disease in at least one family (Tomlinson et al., 2002). Further studies show that N107T is located around the highly conserved active site of the protein (Picaud et al., 2011). The N107T 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 population. This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar 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. Based on the currently available evidence, we consider N107T to be pathogenic, and its presence consistent with a risk to develop features of HLRCC
Invitae RCV000813168 SCV000953513 pathogenic Fumarase deficiency 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces asparagine with threonine at codon 107 of the FH protein (p.Asn107Thr). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in numerous individuals and families affected with hereditary leiomyomatosis and renal cell cancer (PMID: 24625422, 23211287, 15937070, 16757530, 26900816, 21630274) and was reported to co-segregate with disease in at least one family (PMID: 11865300). This variant is also known as c.191A>C, p.Asn64Thr in the literature. ClinVar contains an entry for this variant (Variation ID: 92455). Experimental studies in patient-derived cell lines have shown that this missense change disrupts FH enzymatic activity (PMID: 11865300). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000017620 SCV000037894 pathogenic Multiple cutaneous leiomyomas 2006-08-01 no assertion criteria provided literature only

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