Submissions for variant NM_001065.4(TNFRSF1A):c.1328G>T (p.Gly443Val)

gnomAD frequency: 0.00011  dbSNP: rs201062001

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000709841	SCV000618818	uncertain significance	not provided	2017-07-03	criteria provided, single submitter	clinical testing	The G443V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is observed in 3/4788 (0.063%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). G443V 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 not conserved. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000795391	SCV000934854	likely benign	TNF receptor-associated periodic fever syndrome (TRAPS)	2024-01-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002159	SCV001160015	uncertain significance	not specified	2018-10-13	criteria provided, single submitter	clinical testing	The TNFRSF1A c.1328G>T; p.Gly443Val variant (rs201062001), to our knowledge, is not reported in the medical literature or gene-specific databases. The variant is listed in the ClinVar database (Variation ID: 450261) and in the general population with an allele frequency of 0.01% (18/156966 alleles) in the Genome Aggregation Database. The glycine at this position is weakly conserved and computational analyses (SIFT:Damaging, PolyPhen-2:Benign) predict conflicting effects of this variant on protein structure/function. Additionally, there are no pathogenic variants described in this region of the protein (Lobito 2011). However, there is insufficient evidence to classify this variant with certainty. References: 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	RCV000795391	SCV001272399	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263726	SCV002543089	uncertain significance	Autoinflammatory syndrome	2016-12-22	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV000709841	SCV000840171	not provided	not provided		no assertion provided	phenotyping only	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.