ClinVar Miner

Submissions for variant NM_006440.5(TXNRD2):c.1174T>C (p.Tyr392His) (rs201971987)

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Total submissions: 4
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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 Other strong data supporting benign classification;Subpopulation frequency in support of benign classification
GeneDx RCV000435580 SCV000532171 uncertain significance not provided 2018-12-24 criteria provided, single submitter clinical testing The Y392H variant of uncertain significance in the TXNRD2 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 130/276634 (0.05%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). However, the Y392H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000467999 SCV000546079 uncertain significance Primary dilated cardiomyopathy 2020-05-27 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 392 of the TXNRD2 protein (p.Tyr392His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs201971987, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with TXNRD2-related disease. ClinVar contains an entry for this variant (Variation ID: 263636). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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

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