ClinVar Miner

Submissions for variant NM_000143.3(FH):c.521C>G (p.Pro174Arg) (rs199822819)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492836 SCV000581681 pathogenic Hereditary cancer-predisposing syndrome 2018-02-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
CSER_CC_NCGL; University of Washington Medical Center RCV000022554 SCV000190212 likely benign Fumarase deficiency 2014-06-01 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078149 SCV000109987 pathogenic not provided 2013-03-06 criteria provided, single submitter clinical testing
GeneDx RCV000078149 SCV000516751 pathogenic not provided 2015-04-28 criteria provided, single submitter clinical testing The P174R variant in the FH gene has been reported previously using alternative nomenclature (P131R)in individuals with FH-related disorders (Mroch, et al., 2012; Pollard, et al., 2005; Alam, et al., 2003). AnFH-deficient patient reportedly compound heterozygous for the P174R (P131R) variant and a splicevariant was found to have 13% enzyme activity in skin fibroblasts compared to controls (Pollard, et al.,2005). The P174R variant was not observed at any significant frequency in approximately 6,500individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. TheP174R variant is a non-conservative amino acid substitution, which is likely to impact secondary proteinstructure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs ata position that is conserved across species. In silico analysis predicts this variant is probably damaging tothe protein structure/function. We interpret P174R as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000353057 SCV000356712 uncertain significance Multiple cutaneous leiomyomas 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000022554 SCV000356713 likely pathogenic Fumarase deficiency 2017-04-27 criteria provided, single submitter clinical testing The FH c.521C>G (p.Pro174Arg) missense variant has been reported in three studies in which it is found in a compound heterozygous state in four individuals with fumarate hydratase, two of whom were siblings with a severe phenotype who carried the p.Pro174Arg variant and a deletion in the FH gene (Alam et al. 2003; Mroch et al. 2012; Kimonis et al. 2012). Control data are unavailable for the p.Pro174Arg variant, which is reported at a frequency of 0.00045 in the African American population of the Exome Sequencing Project but this is based on two alleles only in a region of good sequencing coverage so the variant is presumed rare. Functional studies in patient skin fibroblasts and cells lines showed that the variant resulted in between 13 - 25% fumarase activity compared to controls (Alam et al. 2003; Kimonis et al. 2012). Based on the evidence the p.Pro174Arg variant is classified as likely pathogenic for fumarate hydratase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Clinical Services Laboratory,Illumina RCV000304166 SCV000356714 uncertain significance Multiple Cutaneous and Uterine Leiomyomas 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000022554 SCV000283674 pathogenic Fumarase deficiency 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 174 of the FH protein (p.Pro174Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs199822819, ExAC 0.003%). This variant has been reported to be in trans with other pathogenic FH variants in individuals affected with autosomal recessive fumarase deficiency (PMID: 12761039, 22069215). Also, an individual with mild fumarase deficiency was reported to be homozygous for this variant (PMID: 16575891). Parents identified to be heterozygous for this variant did not have hereditary leiomyomatosis and renal cell cancer (HLRCC) at the time of evaluation (PMID: 12761039, 22069215, 16575891). This sequence change is also known as c.392C>G (p.Pro131Arg) in the literature. ClinVar contains an entry for this variant (Variation ID: 29705). Biochemical studies on patients affected with fumarase deficiency carrying this variant in trans with another pathogenic FH variant showed grossly increased excretion of fumaric acid and substantially reduced fumarase activity in their fibroblast cells (PMID: 22595425, 12761039, 16575891). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000022554 SCV000043843 pathogenic Fumarase deficiency 2012-01-01 no assertion criteria provided literature only

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