ClinVar Miner

Submissions for variant NM_001099274.3(TINF2):c.844C>T (p.Arg282Cys) (rs121918545)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000434257 SCV000514903 pathogenic not provided 2018-05-17 criteria provided, single submitter clinical testing The R282C variant has been reported previously in multiple patients with dyskeratosis congenita, including one instance in which it occurred de novo (Vulliamy et al., 2012; O'Connell et al., 2014; Isoda et al., 2013; Walne et al., 2008). It was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R282C 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. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Although co-immunoprecipitation assays of the R282C variant suggest that it may not have a negative impact on the shelterin protein complex (Xin et al., 2012), missense variants at the same (R282G/S/L/H) and in nearby residues (K280E, E281K, P283S/A/H, T284A, L287P) have been reported in the Human Gene Mutation Database in association with dyskeratosis congenita (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret the R282C variant as pathogenic.
Invitae RCV001054196 SCV001218499 pathogenic Dyskeratosis congenita 2019-04-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 282 of the TINF2 protein (p.Arg282Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with dyskeratosis congenita or TINF2-related disease (PMID: 18669893, 19090550, 21199492, 26859482, 29742735, 23094712). ClinVar contains an entry for this variant (Variation ID: 5627). This variant has been reported not to substantially affect binding to protein partners of the shelterin complex, but the clinical significance of this finding is uncertain (PMID: 22211879). This variant disrupts the p.Arg282 amino acid residue in TINF2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18669893, 18252230 21536674). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000005981 SCV000026163 pathogenic Dyskeratosis congenita, autosomal dominant, 3 2008-11-01 no assertion criteria provided literature only
GeneReviews RCV000032169 SCV000055748 pathologic Dyskeratosis congenita, autosomal dominant 1 2012-05-10 no assertion criteria provided curation Converted during submission to Pathogenic.

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