Submissions for variant NM_005546.4(ITK):c.1741C>T (p.Arg581Trp)

gnomAD frequency: 0.00045  dbSNP: rs34482255

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000650370	SCV000455878	likely benign	Lymphoproliferative syndrome 1	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.
Invitae	RCV000650370	SCV000772213	likely benign	Lymphoproliferative syndrome 1	2024-01-16	criteria provided, single submitter	clinical testing
GeneDx	RCV001786380	SCV002028985	uncertain significance	not provided	2021-04-26	criteria provided, single submitter	clinical testing	Identified in individuals with hemophagocytic lymphohistiocytosis in the published literature, however, no additional information was provided (Miao et al., 2019); Identified in the heterozygous state in patients with primary Sjogren's syndrome and with natural killer/T-cell lymphoma in the published literature, however, this variant was also identified in unaffected individuals in these families (Wang et al., 2020; Li et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24448499, 31848144, 32874983, 30899265)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263636	SCV002543500	uncertain significance	Autoinflammatory syndrome	2018-04-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001786380	SCV004698997	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	ITK: PM5, BS2
PreventionGenetics, part of Exact Sciences	RCV003932447	SCV004755334	benign	ITK-related disorder	2019-07-02	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).