ClinVar Miner

Submissions for variant NM_001128228.3(TPRN):c.2023G>A (p.Ala675Thr)

gnomAD frequency: 0.00070  dbSNP: rs139520402
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000214630 SCV000270936 likely benign not specified 2016-03-15 criteria provided, single submitter clinical testing p.Ala675Thr in exon 3 of TPRN: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, >25 mammals have a threonine (Thr) at this position despite high nearby amin o acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. It has been identified in 0.1% (65/6 4212) European chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs139520402).
GeneDx RCV000842759 SCV000984790 likely benign not provided 2021-01-05 criteria provided, single submitter clinical testing
Invitae RCV000842759 SCV002113844 uncertain significance not provided 2023-11-27 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 675 of the TPRN protein (p.Ala675Thr). This variant is present in population databases (rs139520402, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TPRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 228025). 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 TPRN 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.
Division of Human Genetics, Children's Hospital of Philadelphia RCV000477812 SCV000536789 uncertain significance Autosomal recessive nonsyndromic hearing loss 79 2016-09-07 no assertion criteria provided research

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