Submissions for variant NM_001099274.3(TINF2):c.845G>A (p.Arg282His)

dbSNP: rs121918544

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000005978	SCV000249157	pathogenic	Dyskeratosis congenita, autosomal dominant 3	2015-07-07	criteria provided, single submitter	clinical testing
Degerman lab, Umeå University	RCV000005978	SCV000611706	pathogenic	Dyskeratosis congenita, autosomal dominant 3	2017-11-23	criteria provided, single submitter	clinical testing
Invitae	RCV001382425	SCV001581189	pathogenic	Dyskeratosis congenita	2023-05-11	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with dyskeratosis congenita (PMID: 18252230, 18669893). Experimental studies have shown that this missense change affects TINF2 function (PMID: 21477109, 21536674, 29581185). 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. ClinVar contains an entry for this variant (Variation ID: 5625). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 282 of the TINF2 protein (p.Arg282His). For these reasons, this variant has been classified as Pathogenic. 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, 19090550, 21199492, 23094712, 26859482, 29742735). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
Mayo Clinic Laboratories, Mayo Clinic	RCV001509450	SCV001716177	pathogenic	not provided	2021-03-30	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM1, PM2_supporting, PP3
Ambry Genetics	RCV001382425	SCV002676023	pathogenic	Dyskeratosis congenita	2016-12-20	criteria provided, single submitter	clinical testing	The p.R282H pathogenic mutation (also known as c.845G>A), located in coding exon 6 of the TINF2 gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by histidine, an amino acid with highly similar properties.This pathogenic mutation was first reported in three unrelated individuals with dyskeratosis congenita (DC) and very short telomeres (Savage SA et al. Am. J. Hum. Genet., 2008 Feb;82:501-9). Another study identified this mutation in an additional 14 individuals with DC and short telomeres; parental testing determined the majority of the identified mutations were de novo occurrences. In this cohort, individuals with this pathogenic mutation had clinically severe presentations, including individuals with Revesz syndrome and Hoyeraal-Hreidarsson syndrome (Walne AJ et al. Blood, 2008 Nov;112:3594-600). An in vitro functional study found this pathogenic mutation lead to telomere shortening, but did not affect telomerase activity, total levels of TERC, ,or cell proliferation; the authors propose telomere shortening may occur due to a defect in telomerase trafficking (Yang D et al. J. Biol. Chem., 2011 Jul;286:23022-30). Based on the supporting evidence, p.R282H is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002490324	SCV002796913	pathogenic	Revesz syndrome; Dyskeratosis congenita, autosomal dominant 1; Dyskeratosis congenita, autosomal dominant 3	2022-04-02	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000005978	SCV003842251	pathogenic	Dyskeratosis congenita, autosomal dominant 3		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.845G>A in Exon 6 of the TINF2 gene that results in the amino acid substitution p.Arg282His was identified. The observed variant has a minor allelefrequency of 0.000% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individualtools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for anindividual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 5625 as of 2022-12-31). The p.R282H pathogenic mutation (also known as c.845G>A), located in coding exon 6 of the TINF2 gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by histidine, an amino acid with highly similar properties.This pathogenic mutation was first reported in three unrelated individuals with dyskeratosis congenita (DC) and very short telomeres (Savage, Sharon A et al., 2008; Walne, Amanda J et al., 2008; Vulliamy, T et al., 2012). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
OMIM	RCV000005978	SCV000026160	pathogenic	Dyskeratosis congenita, autosomal dominant 3	2012-05-01	no assertion criteria provided	literature only
OMIM	RCV000005979	SCV000026161	pathogenic	Revesz syndrome	2012-05-01	no assertion criteria provided	literature only