Submissions for variant NM_001065.4(TNFRSF1A):c.370G>A (p.Val124Met)

gnomAD frequency: 0.00001  dbSNP: rs104895278

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000215355	SCV000279196	uncertain significance	not provided	2021-11-01	criteria provided, single submitter	clinical testing	Observed in patients with periodic fevers and/or TRAPS in published literature; detailed information is not available for some patients (Lopalco G et al., 2015; Pucino V et al., 2016; Gaggiano C et al., 2020; Cantarini L et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.V95M; This variant is associated with the following publications: (PMID: 26598380, 32831641, 16635178, 21029567, 22311714, 24393624, 25936627)
Invitae	RCV000083949	SCV000931104	uncertain significance	TNF receptor-associated periodic fever syndrome (TRAPS)	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 124 of the TNFRSF1A protein (p.Val124Met). This variant is present in population databases (rs104895278, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with atypical inflammatory phenotypes (PMID: 16635178, 21029567, 22311714, 24393624, 25936627). This variant is also known as p.Val95Met or V95M. ClinVar contains an entry for this variant (Variation ID: 97696). 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.
Mendelics	RCV000083949	SCV001138633	uncertain significance	TNF receptor-associated periodic fever syndrome (TRAPS)	2019-05-28	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262671	SCV002543101	uncertain significance	Autoinflammatory syndrome	2019-09-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000215355	SCV004699830	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing	TNFRSF1A: PS4:Moderate, PM6:Supporting
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000083949	SCV000116065	not provided	TNF receptor-associated periodic fever syndrome (TRAPS)		no assertion provided	not provided