Submissions for variant NM_198253.3(TERT):c.2147C>T (p.Ala716Val)

dbSNP: rs199422298

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514132	SCV001546994	pathogenic	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 716 of the TERT protein (p.Ala716Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TERT-related conditions (PMID: 18931339, 21931702, 29146883; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39109). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TERT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TERT function (PMID: 18931339, 21931702). This variant disrupts the p.Ala716 amino acid residue in TERT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30203795). 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.
GeneDx	RCV001576802	SCV001804059	pathogenic	not provided	2020-03-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced telomerase activity and telomere length (Du 2009, Vulliamy 2011); Not observed in large population cohorts (Lek 2016); 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: 29596117, 18931339, 21931702, 23618685, 29146883, 20301779, 23538340)
Ambry Genetics	RCV004558279	SCV002731191	likely pathogenic	Dyskeratosis congenita	2017-05-10	criteria provided, single submitter	clinical testing	The p.A716V variant (also known as c.2147C>T), located in coding exon 6 of the TERT gene, results from a C to T substitution at nucleotide position 2147. The alanine at codon 716 is replaced by valine, an amino acid with similar properties. This variant was previously identified in a child with severe pancytopenia and a significant family history of aplastic anemia and lung disease; the p.A716V variant showed a significant reduction in telomerase activity (14% of wild type), and telomere length was determined to be below the 1st percentile of normal controls for this patient (Du HY et al. Blood., 2009 Jan;113(2):309-16). In our internal cohort, this variant was detected in an individual with aplastic anemia, pulmonary fibrosis, and exudative retinopathy. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786285	SCV005400290	pathogenic	Dyskeratosis congenita, autosomal dominant 2	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal dominant dyskeratosis congenita 2 and autosomal recessive dyskeratosis congenita 4 (MIM#613989) and telomere-related pulmonary fibrosis and/or bone marrow failure 1 (MIM#614742). (I) 0108 - This gene is associated with both recessive and dominant disease. No specific genotype-phenotype correlations have been established (PMID: 20301779). (I) 0115 - Variants in this gene are known to have variable expressivity. Phenotypic variability is well reported for dyskeratosis congenita (PMID: 20301779). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Ala716Thr) has been reported as pathogenic by multiple clinical testing laboratories (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic/pathogenic by multiple clinical testing laboratories (ClinVar). It has also been reported in multiple unrelated individuals with cytopenia, aplastic anaemia or bone marrow failure, including heterozygotes without a known 2nd variant in this gene (PMIDs: 18931339, 21931702, 29596117, 33003434, 34565437). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Reduced telomere length has been reported in affected individuals with this variant (PMIDs: 18931339, 21931702). In addition, telomeric repeat amplification protocol (TRAP) assay using transfected cells showed this variant resulted in reduced telomerase activity (PMIDs: 18931339, 21931702). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneReviews	RCV000032376	SCV000056032	not provided	Aplastic anemia		no assertion provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001576802	SCV001956304	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001576802	SCV001970409	likely pathogenic	not provided		no assertion criteria provided	clinical testing