Submissions for variant NM_001065.4(TNFRSF1A):c.935G>A (p.Arg312Lys)

gnomAD frequency: 0.00113  dbSNP: rs200900510

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001703505	SCV000514913	likely benign	not provided	2021-05-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28814775)
Invitae	RCV000537537	SCV000637238	benign	TNF receptor-associated periodic fever syndrome (TRAPS)	2024-01-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001703505	SCV001157935	uncertain significance	not provided	2020-03-10	criteria provided, single submitter	clinical testing	The TNFRSF1A c.935G>A; p.Arg312Lys variant (rs200900510) is reported in the medical literature in an individual with Behcet disease (Burillo-Sanz 2017). The variant is reported in the ClinVar database (Variation ID: 378735) and is listed in the African population with an allele frequency of 0.35% (69/19,970 alleles, including 1 homozygote) in the Genome Aggregation Database. The arginine at this position is moderately conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is tolerated. Additionally, there are few known pathogenic variants in this region of the protein (Lobito 2011). Based on this and the increased population frequency in the African population, it is unlikely that this is a high penetrance pathogenic variant. However, we cannot rule out the possibility that this is a low penetrance variant without additional information. Therefore, considering available information, this variant is classified as a variant of uncertain significance. References: Burillo-Sanz S et al. Mutational profile of rare variants in inflammasome-related genes in Behcet disease: A Next Generation Sequencing approach. Sci Rep. 2017 Aug 16;7(1):8453. Lobito AA et al. Disease causing mutations in the TNF and TNFR superfamilies: Focus on molecular mechanisms driving disease. Trends Mol Med. 2011 Sep;17(9):494-505.
Illumina Laboratory Services, Illumina	RCV000537537	SCV001267911	likely benign	TNF receptor-associated periodic fever syndrome (TRAPS)	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263679	SCV002543116	likely benign	Autoinflammatory syndrome	2021-01-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001703505	SCV003917177	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	TNFRSF1A: BP4, BS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317207	SCV004020771	uncertain significance	not specified	2023-06-21	criteria provided, single submitter	clinical testing	Variant summary: TNFRSF1A c.935G>A (p.Arg312Lys) results in a conservative amino acid change in 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 0.00053 in 218402 control chromosomes in the gnomAD database, including 1 homozygotes. c.935G>A has been reported in the literature in individuals affected with Bechet Disease (Burillo-Sanz_2017) and Idiopathic Chronic Pancreatitis (Sofia_2016). These reports do not provide unequivocal conclusions about association of the variant with TNF Receptor-Associated Periodic Fever Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28814775, 27264265). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=5), VUS (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Immunology, Hospital Universitario Virgen del Rocio	RCV000458191	SCV000503001	pathogenic	Behcet disease	2017-02-22	no assertion criteria provided	case-control