ClinVar Miner

Submissions for variant NM_000143.3(FH):c.7C>G (p.Arg3Gly) (rs202166344)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000568788 SCV000673354 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000195609 SCV000251490 uncertain significance not provided 2018-10-29 criteria provided, single submitter clinical testing This variant is denoted FH c.7C>G at the cDNA level, p.Arg3Gly (R3G) at the protein level, and results in the change of an Arginine to a Glycine (CGA>GGA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. FH Arg3Gly was observed at an allele frequency of 0.02% (13/66,996) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether FH Arg3Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000204400 SCV000356748 uncertain significance Fumarase deficiency 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000346414 SCV000356749 uncertain significance Multiple cutaneous leiomyomas 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000399999 SCV000356750 uncertain significance Multiple Cutaneous and Uterine Leiomyomas 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000204400 SCV000262348 uncertain significance Fumarase deficiency 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 3 of the FH protein (p.Arg3Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. While this variant is present in population databases (rs202166344), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with FH-related disease. ClinVar contains an entry for this variant (Variation ID: 214430). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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