Submissions for variant NM_001065.4(TNFRSF1A):c.334G>A (p.Val112Met)

gnomAD frequency: 0.00007  dbSNP: rs201753543

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000756795	SCV000279194	uncertain significance	not provided	2014-10-28	criteria provided, single submitter	clinical testing	The V112M variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. The V112M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense mutation at the same residue (V112L) has been reported in association with periodic fever (Lobito et al., 2011), using alternative nomenclature. In addition, the V112L variant and another conservative missense change (V112G) have been observed in two individuals previously tested one of whom also harbored another missense variant. Based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999868	SCV000884708	uncertain significance	not specified	2019-05-03	criteria provided, single submitter	clinical testing	The TNFRSF1A c.334G>A;p.Val112Met variant (also known as V83M) has not been listed in the medical literature, but is listed in a gene-specific database in a symptomatic individual (see link below). Another variant in the same amino acid, c.334G>T;p.Val112Leu (also known as V83L), has been published in the medical literature in an individual reportedly with a periodic fever syndrome (Lobito 2011). The variant is listed in the dbSNP variant database (rs201753543) with an allele frequency of 0.0154 percent (2/13004 alleles) in the Exome Variant Server and 0.005281 percent (13/246160 alleles) in the Genome Aggregation Database. The valine at this position occurs in a conserved functional domain, and is well conserved, but computational algorithms (PolyPhen2, SIFT) predict this variant is tolerated. Considering available information, there is insufficient evidence to classify this variant with certainty.
Invitae	RCV000823924	SCV000964798	uncertain significance	TNF receptor-associated periodic fever syndrome (TRAPS)	2023-08-10	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TNFRSF1A protein function. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 234422). This variant has not been reported in the literature in individuals affected with TNFRSF1A-related conditions. This variant is present in population databases (rs201753543, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 112 of the TNFRSF1A protein (p.Val112Met).
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262825	SCV002543096	uncertain significance	Autoinflammatory syndrome	2016-12-12	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000756795	SCV004026393	uncertain significance	not provided	2023-07-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003977628	SCV004793149	uncertain significance	TNFRSF1A-related disorder	2023-10-26	criteria provided, single submitter	clinical testing	The TNFRSF1A c.334G>A variant is predicted to result in the amino acid substitution p.Val112Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0097% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-6442671-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.