Submissions for variant NM_198253.3(TERT):c.1234C>T (p.His412Tyr)

gnomAD frequency: 0.00316  dbSNP: rs34094720

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000218461	SCV000270914	likely benign	not specified	2015-02-24	criteria provided, single submitter	clinical testing	p.His412Tyr in exon 2 of TERT: This variant is not expected to have clinical sig nificance because it has been identified in 1.5% (115/7512) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs34094720). In addition, the histidine (His) residue at position 412 is no t conserved in mammals and other evolutionarily distant species, and the change to tyrosine (Tyr) is present in 2 mammals.
Invitae	RCV002513014	SCV000291844	benign	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000032365	SCV000452694	likely benign	Aplastic anemia	2017-04-27	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000262966	SCV000452695	likely benign	Dyskeratosis congenita, autosomal dominant 2	2017-04-27	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000013567	SCV000452696	likely benign	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1	2017-04-27	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000425346	SCV000511855	likely benign	not provided	2016-11-15	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Genetic Services Laboratory, University of Chicago	RCV000218461	SCV000597454	benign	not specified	2018-11-06	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000218461	SCV000706965	likely benign	not specified	2017-03-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000425346	SCV001801383	likely benign	not provided	2020-08-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28495692, 31871297, 31268371, 29483670, 29416752, 30791107, 15814878, 29146883, 19147845, 19760749, 26576048, 27153395, 27111861, 23716176, 18753630, 23901009, 18042801, 23538340)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000425346	SCV002010312	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002255259	SCV002533100	benign	Dyskeratosis congenita	2020-03-26	criteria provided, single submitter	curation
Ambry Genetics	RCV002362581	SCV002665134	uncertain significance	Dyskeratosis congenita; Hereditary cancer-predisposing syndrome	2017-08-29	criteria provided, single submitter	clinical testing	The p.H412Y variant (also known as c.1234C>T), located in coding exon 2 of the TERT gene, results from a C to T substitution at nucleotide position 1234. The histidine at codon 412 is replaced by tyrosine, an amino acid with similar properties. This variant was first described in two unrelated adults with moderate to severe aplastic anemia. In cells transfected with this variant, telomerase activity decreased to approximately 50% of wild type, whereas other alterations studied resulted in activity levels of <1% of wild type (Yamaguchi H et al. N. Engl. J. Med., 2005 Apr;352:1413-24). In addition, this variant was found in an individual with pulmonary fibrosis, pulmonary hypertension and a telomere length 25% shorter than healthy individuals and this individual's father with idiopathic pulmonary fibrosis (Marchand-Adam S et al. Am. J. Respir. Crit. Care Med., 2013 Aug;188:402-4). In another study, this variant was detected in trans with the p.P704S alteration in the TERT gene in an individual with osteoporosis, short telomeres, and normal peripheral blood cell counts. This individual&rsquo;s son was homozygous for the p.P704S alteration and presented with characteristic features of dyskeratosis congenita. Functional analysis of the the p.H412Y variant demonstrated a reduced telomerase activity of 36% of wild type (Du HY et al. Blood, 2008 Feb;111:1128-30). Additional functional studies showed that the p.H412Y variant resulted in a 15% decrease in activity in vitro (Alder JK et al. Proc. Natl. Acad. Sci. U.S.A., 2008 Sep;105:13051-6), whereas another study showed no change in activity or processivity in vitro or in human cell lines (Zaug AJ et al. Nucleic Acids Res., 2013 Oct;41:8969-78). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224095	SCV003920547	likely benign	Acute myeloid leukemia; Dyskeratosis congenita, autosomal dominant 2; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1; Melanoma, cutaneous malignant, susceptibility to, 9	2022-11-09	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in at least 6 individuals with varying phenotypes (aplastic anemia, idiopathic interstitial pneumonias, hypoxemia, diffuse cutaneous systemic sclerosis, and bone marrow failure) (Yamaguchi 2005 PMID:15814878, Alder 2008 PMID:18753630, Sugino 2015 PMID:26576048, Mak 2016 PMID:27111861, Bluteau 2018 PMID:29146883). However, this variant is present in 0.4% (384/83108) of European alleles, including 2 homozygotes, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-1293767-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar, with several labs classifying this variant as likely benign or benign (Variation ID:12730). Evolutionary conservation suggests that this variant may not impact the protein; computational predictive tools for this variant are unclear. Functional studies for this variant have reported a wide range of outcomes from a reduction in activity to 36% of wild-type to near normal activity (Yamaguchi 2005 PMID:15814878, Alder 2008 PMID:18753630, Du 2008 PMID:18042801, Zaug 2013 PMID:23901009). In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore, this variant is classified as Likely Benign.
CeGaT Center for Human Genetics Tuebingen	RCV000425346	SCV004153872	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	TERT: PP2, BS3:Supporting, BS1
OMIM	RCV000013567	SCV000033814	pathogenic	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1	2008-02-01	no assertion criteria provided	literature only
GeneReviews	RCV000032365	SCV000056021	not provided	Aplastic anemia		no assertion provided	literature only
OMIM	RCV000190902	SCV000245776	pathogenic	Autosomal recessive dyskeratosis congenita 4	2008-02-01	no assertion criteria provided	literature only