Submissions for variant NM_198253.3(TERT):c.604G>A (p.Ala202Thr)

gnomAD frequency: 0.00018  dbSNP: rs121918661

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513013	SCV000551526	likely benign	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000489117	SCV000577668	likely benign	not provided	2021-06-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15885610, 23538340, 23716176, 15814878, 30791107, 30426156, 29416752, 30523342, 20858879, 32089214, 22424236, 23901009)
Genetic Services Laboratory, University of Chicago	RCV000604322	SCV000597471	uncertain significance	not specified	2019-10-24	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000604322	SCV000711360	uncertain significance	not specified	2017-04-14	criteria provided, single submitter	clinical testing	The p.Ala202Thr (NM_198253.2 c.604G>A) variant in TERT has been reported in hete rozygosity in 2 individuals with clinical features of Dyskeratosis congenita an d related disorders (Yamaguchi 2005; ClinVar Variation ID#12729). It was also id entified in another family and did not segregate with disease ( Vulliamy 2005). This variant has been identified in 0.205% (13/6,346) of Latino chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1 21918661). In vitro functional studies reportedly suggest that the p.Ala202Thr v ariant may impact protein function (Zaug 2013 and Yamaguchi 2005); however, thes e types of assays may not accurately represent biological function. The amino ac id position is not conserved in mammals and most computational predictions progr ams do not suggest an impact. In summary, the clinical significance of the p.Ala 202Thr variant is uncertain significance.
Eurofins Ntd Llc (ga)	RCV000489117	SCV000857418	uncertain significance	not provided	2017-10-10	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000758251	SCV000886891	likely benign	Dyskeratosis congenita, autosomal dominant 2	2019-02-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000032398	SCV001318822	uncertain significance	Aplastic anemia	2018-01-25	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000758251	SCV001318823	uncertain significance	Dyskeratosis congenita, autosomal dominant 2	2018-01-25	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000013566	SCV001318824	benign	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1	2018-01-25	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000758251	SCV001429338	uncertain significance	Dyskeratosis congenita, autosomal dominant 2	2020-01-24	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000604322	SCV001984696	uncertain significance	not specified	2021-03-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002255997	SCV002533158	uncertain significance	Dyskeratosis congenita	2021-10-31	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000758251	SCV002584574	uncertain significance	Dyskeratosis congenita, autosomal dominant 2	2022-08-23	criteria provided, single submitter	clinical testing	The TERT c.604G>A (p.Ala202Thr) missense change has a maximum subpopulation frequency of 0.085% in gnomAD v2.1.1 including one homozygote (https://gnomad.broadinstitute.org/). This variant has been reported as heterozygous in individuals with a personal and/or family history of aplastic anemia and myelodysplastic syndrome (PMID: 15814878, 30523342) and was found to segregate with short telomeres in one family (PMID: 15814878). This variant has also been reported as homozygous in an individual with oligodontia, abnormality of the fingernails, hidrotic ectodermal dysplasia, sparse hair, dystrophic fingernails (PMID: 27848944). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and functional studies have shown telomerase activity at reduced to approximately 50-80% of WT (PMID: 15814878, 23901009). In summary, the evidence currently available is insufficient to determine the role of this variant in dyskeratosis congenita. It has therefore been classified as of uncertain significance.
Ambry Genetics	RCV002255997	SCV002654897	uncertain significance	Dyskeratosis congenita	2018-01-22	criteria provided, single submitter	clinical testing	The p.A202T variant (also known as c.604G>A), located in coding exon 2 of the TERT gene, results from a G to A substitution at nucleotide position 604. The alanine at codon 202 is replaced by threonine, an amino acid with similar properties. This variant was identified in individuals with aplastic anemia (Yamaguchi H et al. N. Engl. J. Med., 2005 Apr;352:1413-24; Scheinberg P et al. JAMA, 2010 Sep;304:1358-64) as well as in healthy individuals (Calado RT et al. Blood, 2009 Sep;114:2236-43; Chen R et al. Cell, 2012 Mar;148:1293-307). In addition, telomerase activity studies have had conflicting results, with <1% activity in one assay and 88% in another compared to wild type (Yamaguchi H et al. N. Engl. J. Med., 2005 Apr;352:1413-24; Zaug AJ et al. Nucleic Acids Res., 2013 Oct;41:8969-78). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000489117	SCV003827182	uncertain significance	not provided	2023-02-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000604322	SCV004243183	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
OMIM	RCV000013566	SCV000033813	pathogenic	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1	2005-04-07	no assertion criteria provided	literature only
GeneReviews	RCV000032398	SCV000056054	not provided	Aplastic anemia		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000489117	SCV001744189	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000489117	SCV001797328	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000489117	SCV001808998	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000489117	SCV001970479	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541000	SCV004785488	likely benign	TERT-related disorder	2022-11-11	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).