ClinVar Miner

Submissions for variant NM_001065.4(TNFRSF1A):c.362G>A (p.Arg121Gln) (rs4149584)

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Total submissions: 12
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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 2018-06-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001281886 SCV000605409 benign none provided 2020-07-08 criteria provided, single submitter clinical testing
Invitae RCV000200263 SCV000637237 benign TNF receptor-associated periodic fever syndrome (TRAPS) 2020-12-02 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) 2019-09-16 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.
Mendelics RCV000200263 SCV001138634 benign TNF receptor-associated periodic fever syndrome (TRAPS) 2019-05-28 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV001280954 SCV001468326 uncertain significance TNF receptor-associated periodic fever syndrome (TRAPS); Multiple sclerosis, susceptibility to, 5 2020-03-20 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000487915 SCV001548647 uncertain significance not provided no assertion criteria provided clinical testing The TNFRSF1A p.Arg121Gln variant has been reported multiple times in association with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) (Ruiz-Ortiz_2017_PMID:28396659; Shinar_2012_PMID:22661645; Mühlenen_2015). The variant was identified in dbSNP (ID: rs4149584) LOVD 3.0 (classified as a VUS) and ClinVar (classified as benign by Invitae and ARUP Laboratories, as likely benign by CeGaT Praxis fuer Humangenetik Tuebingen, as uncertain significance by Laboratory for Molecular Medicine, GeneDx, EGL Genetic Diagnostics and Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, as likely pathogenic by Department of Genetics, Sultan Qaboos University Hospital, Oman and as pathogenic by UCLA Clinical Genomics Center, UCLA). The variant was identified in control databases in 3646 of 282618 chromosomes (29 homozygous) at a frequency of 0.0129 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 2564 of 129036 chromosomes (freq: 0.01987), Ashkenazi Jewish in 184 of 10368 chromosomes (freq: 0.01775), Other in 125 of 7226 chromosomes (freq: 0.0173), European (Finnish) in 265 of 25094 chromosomes (freq: 0.01056), Latino in 319 of 35430 chromosomes (freq: 0.009004), South Asian in 111 of 30604 chromosomes (freq: 0.003627) and African in 78 of 24916 chromosomes (freq: 0.003131), but was not observed in the East Asian population. The p.Arg121Gln residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional studies provide inconsistent results regarding altered protein function (Aksentijevich_2001_PMID:11443543; Agulló_2015_PMID:26616867). This variant has been previously reported as pathogenic, however due to the high frequency in control populations may be a low penetrant or benign variant. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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