ClinVar Genomic variation as it relates to human health

Observed together with a pathogenic variant in the MEFV gene in a patient with overlapping FMF and TRAPS phenotypes (Neocleous et al., 2016); also identified in patients heterozygous for a pathogenic variant in MEFV or NLRP3 at GeneDx; Variant frequency was not shown to differ between controls and the affected population (D'Osualdo et al., 2006); Functional studies have shown that this variant does not affect protein expression and localization or its interaction with TNF, but it results in a decrease of cellular inflammatory response (Lobito et al., 2006; Greco et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11443543, 21153350, 22799488, 29599418, 30407166, 16508982, 23117241, 21225694, 17234651, 22887853, 16684962, 21420073, 24286006, 20675856, 21565411, 25333069, 20876156, 19525953, 18287568, 23624563, 23894535, 23079392, 20576331, 21785959, 24393624, 25888769, 25866490, 16569687, 27884173, 26616867, 15657603, 27535533, 25936627, 23461592, 27332769, 28396659, 28361096, 28927886, 27990755, 26598380, 17949559, 17038455, 27994174, 29256170, 29950375, 31365210, 31028937, 31562507, 31422021, 32199921, 31586650, 32143951)

The p.Arg121Gln variant in TNFRSF1A is classified as likely benign because it has been identified in 1.8% (555/29600) of Ashkenazi Jewish chromosomes, including 235 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). ACMG/AMP Criteria applied: BS1.

TNFRSF1A: BP4, BS1, BS2

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.

Variant summary: TNFRSF1A c.362G>A (p.Arg121Gln) results in a conservative amino acid change located in the TNFR/NGFR cysteine-rich region (IPR001368) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.013 in 282618 control chromosomes (gnomAD), including 29 homozygotes. The variant occurs predominantly at a frequency of 0.02 within the Non-Finnish European subpopulation in the gnomAD database, including 24 homozygotes. In a comprehensive characterization of the variant, Lobito_2006 demonstrated that the variant behaved similarly to the wild-type using various assays (e.g. cell surface expression, folding and association with wild-type receptors, secretion, trafficking, apoptosis inhibition). Eleven ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, five as uncertain significance, and five as benign. Based on the evidence outlined above, the variant was classified as benign.

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.

The TNFRSF1A c.362G>A(p.(Arg121Gln) missense variant, also referred to as p.(Arg92Gln), is one of the most common variants associated with familial periodic fever (FPF) and has been identified in many individuals with a phenotype consistent with FPF (Aksentijevich et al. 2001; Ravet et al. 2006; Karatsourakis et al. 2014; Chandrakasan et al. 2014; Lachmann et al. 2014). The variant has been shown to segregate with disease with significantly reduced penetrance (Ravet et al. 2006; Lachmann et al. 2014). The highest frequency of this allele in the Genome Aggregation Database is 0.01987 in the European (non-Finnish) population including 29 homozygotes (version 2.1.1). Based on the conflicting evidence the c.362G>A(p.(Arg121Gln) variant is classified as a variant of uncertain significance for familial periodic fever.

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.

Variant interpreted as Uncertain significance and reported on 01-18-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.