Submissions for variant NM_003235.5(TG):c.8026C>T (p.Arg2676Trp)

gnomAD frequency: 0.00038  dbSNP: rs114613744

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000949747	SCV001096013	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001163834	SCV001325915	uncertain significance	Iodotyrosyl coupling defect	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.
GeneDx	RCV000949747	SCV001816953	uncertain significance	not provided	2023-01-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003489978	SCV004241371	likely benign	not specified	2023-12-20	criteria provided, single submitter	clinical testing	Variant summary: TG c.8026C>T (p.Arg2676Trp) results in a non-conservative amino acid change located in the Carboxylesterase, type B domain (IPR002018) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00055 in 1614192 control chromosomes in the gnomAD database, including 6 homozygotes. This frequency does not allow for any conclusion about variant significance, but the presence of 6 homozygotes without evidence of severe, early-onset disease suggests that this variant is unlikely to be associated with disease. c.8026C>T has been reported in the literature in an individual with ductal plate malformations (Courcet_2015). However, this report does not provide unequivocal conclusions about association of the variant with TG-Related Disorders due to the presence of multiple other detected variants, including variants in the PKHD1 gene that the authors consider to be of greater potential relevance to the phenotype. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26385851). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Two classified the variant as uncertain significance, and one classified the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001163834	SCV004808110	uncertain significance	Iodotyrosyl coupling defect	2024-03-29	criteria provided, single submitter	clinical testing