Submissions for variant NM_006440.5(TXNRD2):c.1174T>C (p.Tyr392His)

gnomAD frequency: 0.00052  dbSNP: rs201971987

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000244103	SCV000318723	likely benign	Cardiovascular phenotype	2020-02-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000435580	SCV000532171	uncertain significance	not provided	2022-08-05	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Invitae	RCV000467999	SCV000546079	uncertain significance	Primary dilated cardiomyopathy	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 392 of the TXNRD2 protein (p.Tyr392His). This variant is present in population databases (rs201971987, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of TXNRD2-related conditions (PMID: 28074886). ClinVar contains an entry for this variant (Variation ID: 263636). 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) performed at Invitae indicates that this missense variant is not expected to disrupt TXNRD2 protein function with a negative predictive value of 80%. 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000435580	SCV001743025	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000435580	SCV001975275	likely benign	not provided		no assertion criteria provided	clinical testing