ClinVar Miner

Submissions for variant NM_001065.3(TNFRSF1A):c.362G>A (p.Arg121Gln) (rs4149584)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UCLA Clinical Genomics Center, UCLA RCV000200263 SCV000255490 pathogenic TNF receptor-associated periodic fever syndrome (TRAPS) 2013-04-02 criteria provided, single submitter clinical testing
GeneDx RCV000222279 SCV000279195 uncertain significance not specified 2017-06-12 criteria provided, single submitter clinical testing The R121Q variant is a common missense change observed in the TNFRSF1A gene. It has been identified in individuals from many different ethnic backgrounds who displayed a milder or atypical clinical presentation of TRAPS (Aksentijevich, 2001; Ravet, 2006; D’Osualdo, 2006; Cantarini et al., 2013). However, it has also been observed in the unaffected control population. In one study, approximately 1% of unaffected controls carried the R121Q variant (Aksentijevich, 2001) and, in more recent study, 4-5% of controls were found to carry this change (Bachetti et al., 2013). Although functional studies have shown that this variant does not affect protein expression and localization or interaction with TNF, it results in an increased cellular inflammatory response (Lobito et al., 2006; Greco et al., 2015). Therefore, it is currently unclear if R121Q is a pathogenic variant with low penetrance and mild symptoms, or a benign variant due to its high frequency in the control population.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000222279 SCV000540561 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Pathogenic by UCLA in ClinVar.Conflicting evidence for disease association. Variant has low penetrance, asymptomatic individuals with the variant have been described. Frequency too high for highly penetrant AD periodic fever. Does not meet criteria for reporting.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487915 SCV000574917 likely benign not provided 2018-09-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000487915 SCV000605409 benign not provided 2017-06-12 criteria provided, single submitter clinical testing
Invitae RCV000200263 SCV000637237 benign TNF receptor-associated periodic fever syndrome (TRAPS) 2017-08-11 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000487915 SCV000704551 uncertain significance not provided 2017-02-07 criteria provided, single submitter clinical testing
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000200263 SCV000891562 likely pathogenic TNF receptor-associated periodic fever syndrome (TRAPS) 2017-12-30 criteria provided, single submitter curation
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000200263 SCV000899035 uncertain significance TNF receptor-associated periodic fever syndrome (TRAPS) 2018-11-05 criteria provided, single submitter clinical testing TNFRSF1A NM_001065.3 exon4 p.Arg121Gln (c.362G>A): This variant is well reported in the literature (alternate nomenclature p.Arg92Gln) and identified in several individuals with periodic fever syndrome (Aksentijevich 2001 PMID:11443543, D'Osualdo 2006 PMID:16508982, Ravet 2006 PMID:16569687, Pelagatti 2011 PMID:21225694, Cantarini 2013 PMID:23745996). However, in all literature reviewed, the phenotype of individuals with this variant is consistently reported as mild with several authors suggesting this is a low penetrance, variable mutation. At least 1 nonsegregation was also identified (Ravet 2006 PMID:16569687). This variant is present in 2% (2510/126556) of European alleles, including 24 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs4149584). This variant is present in ClinVar (Variation ID:217017). This variant amino acid Glutamine (Gln) is present in >15 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In vitro functional studies are conflicting and do not strongly predict that this variant will impact the protein (Aksentijevich 2001 PMID:11443543, D'Osualdo 2006 PMID:16508982, Greco 2015 PMID:25888769). However, these studies may not accurately represent in vivo biological function and further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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