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

dbSNP: rs121918545

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000434257	SCV000514903	pathogenic	not provided	2024-01-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26859482, 21199492, 19090550, 29742735, 30523342, 23094712, 22211879, 27033759, 21659346, 18669893, 24168326, 23242325, 34573280, 32054657, 34522616)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001054196	SCV001218499	pathogenic	Dyskeratosis congenita	2024-06-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 282 of the TINF2 protein (p.Arg282Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dyskeratosis congenita or TINF2-related disease (PMID: 18669893, 19090550, 21199492, 23094712, 26859482, 29742735, 30523342). ClinVar contains an entry for this variant (Variation ID: 5627). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TINF2 function (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: 18252230, 18669893, 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.
Genetic Services Laboratory, University of Chicago	RCV000434257	SCV002069638	pathogenic	not provided	2020-11-19	criteria provided, single submitter	clinical testing	DNA sequence analysis of the TINF2 gene demonstrated a sequence change, c.844C>T, in exon 6 that results in an amino acid change, p.Arg282Cys. This sequence change has not been described in population databases (gnomAD, ExAC); however, it has been observed in several individuals with dyskeratosis congenita and aplastic anemia (PMIDs: 19090550, 21199492, 26859482, 18669893, 29742735, 23094712, 30523342). Additionally, several other sequence changes at the same location have been reported to be pathogenic (PMIDs: 18669893, 18252230, 21536674). The p.Arg282Cys change affects a highly conserved amino acid residue located in a domain of the TINF2 protein that is not known to be functional. The p.Arg282Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies have demonstrated that this sequence change does not impact protein binding in the shelterin complex, however the clinical significance of this finding is unknown at this time (PMID: 22211879). These collective evidences suggest that this sequence change is likely pathogenic.
3billion	RCV000005981	SCV002573273	pathogenic	Dyskeratosis congenita, autosomal dominant 3	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 0.70). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000005627 ) and different missense changes at the same codon (p.Arg282His, p.Arg282Ser / ClinVar ID: VCV000005625 , VCV000005626 ) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV001054196	SCV002678402	pathogenic	Dyskeratosis congenita	2018-12-30	criteria provided, single submitter	clinical testing	The p.R282C pathogenic mutation (also known as c.844C>T), located in coding exon 6 of the TINF2 gene, results from a C to T substitution at nucleotide position 844. The arginine at codon 282 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was reported in multiple individuals with a clinical diagnosis of dyskeratosis congenita; most cases were reportedly de novo (paternity not confirmed); however, some individuals inherited the mutation from an affected parent (Walne AJ et al. Blood, 2008 Nov;112:3594-600; Du H et al. Medicine (Baltimore), 2018 May;97:e0724). This mutation was also described in two unrelated children with severe aplastic anemia (Du HY et al. Pediatr Blood Cancer, 2009 May;52:687). In addition, the most common TINF2 mutation, p.R282H, occurs at the same codon (Sasa GS et al. Clin. Genet., 2012 May;81:470-8). Based on the supporting evidence, p.R282C is interpreted as a disease-causing mutation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000434257	SCV005414214	pathogenic	not provided	2024-04-25	criteria provided, single submitter	clinical testing	PP1, PP3, PM1, PM2, PM5, PS2, PS4
Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology	RCV000005981	SCV005894791	pathogenic	Dyskeratosis congenita, autosomal dominant 3		criteria provided, single submitter	clinical testing
OMIM	RCV000005981	SCV000026163	pathogenic	Dyskeratosis congenita, autosomal dominant 3	2008-11-01	no assertion criteria provided	literature only
GeneReviews	RCV000032169	SCV000055748	not provided	Dyskeratosis congenita, autosomal dominant 1		no assertion provided	literature only