Submissions for variant NM_198253.3(TERT):c.1700C>T (p.Thr567Met)

gnomAD frequency: 0.00001  dbSNP: rs886039438

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255577	SCV000321958	likely pathogenic	not provided	2015-12-08	criteria provided, single submitter	clinical testing	The T567M variant has been published previously in association with Hoyeraal-Hreidarsson syndrome in a family of two homozygous siblings with consanguineous parents (Gramatges et al., 2013). It was not observed in approximately 6,500 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 T567M 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. However, this substitution occurs at a position that is not conserved and in silico analysis predicts this variant likely does not alter the protein structure/function. A missense variants in a nearby residue (K570N) has been reported in the Human Gene Mutation Database in association with Hoyeraal-Hreidarsson syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Studies of the T567M variant have shown that it results in shortened telomeres, reduced telomerase processivity, and therefore Hoyeraal-Hreidarsson syndrome (Gramatges et al., 2013; Liu et al., 2014; Glousker et al., 2015). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002518755	SCV002306696	likely pathogenic	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 567 of the TERT protein (p.Thr567Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of dyskeratosis congenita and/or Hoyeraal Hreidarsson syndrome (PMID: 23538340; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265267). 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 TERT protein function. Experimental studies have shown that this missense change affects TERT function (PMID: 23538340, 34019641). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV004558612	SCV002710149	likely pathogenic	Dyskeratosis congenita	2016-09-29	criteria provided, single submitter	clinical testing	The p.T567M variant (also known as c.1700C>T), located in coding exon 3 of the TERT gene, results from a C to T substitution at nucleotide position 1700. The threonine at codon 567 is replaced by methionine, an amino acid with similar properties. This variant was detected in the homozygous state in a male infant affected with Hoyeraal Hreidarsson syndrome, a form of dyskeratosis congenita. The proband's consanguineous parents each carried one copy of p.T567M and had no clinical symptoms. In addition, the proband's obligate carrier grandfathers had no clinical symptoms, with the exception of a low white blood cell count in one of the grandfathers for several years. Functional analysis in this study showed reduced activity compared to wild type and that this alteration impairs repeat addition processivity (Gramatges MM et al. Blood, 2013 May;121:3586-93). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species, and methionine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.