Submissions for variant NM_001099274.3(TINF2):c.262C>A (p.Pro88Thr)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002047723	SCV002294118	uncertain significance	Dyskeratosis congenita	2021-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline with threonine at codon 88 of the TINF2 protein (p.Pro88Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with TINF2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV003481247	SCV004226506	uncertain significance	not provided	2022-05-12	criteria provided, single submitter	clinical testing	BP4, PM2_supporting
Genetic Services Laboratory, University of Chicago	RCV003151378	SCV003840133	uncertain significance	not specified	2022-08-23	no assertion criteria provided	clinical testing	DNA sequence analysis of the TINF2 gene demonstrated a sequence change, c.262C>A, in exon 2 that results in an amino acid change, p.Pro88Thr. This sequence change does not appear to have been previously described in individuals with TINF2-related disorders and has also not been described in population databases such as ExAC and gnomAD. The p.Pro88Thr change affects a highly conserved amino acid residue located in a domain of the TINF2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro88Thr substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro88Thr change remains unknown at this time.

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