Submissions for variant NM_198253.3(TERT):c.3150G>C (p.Lys1050Asn)

gnomAD frequency: 0.00004  dbSNP: rs373400596

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000344253	SCV000452230	uncertain significance	Dyskeratosis congenita, autosomal dominant 2	2016-08-02	criteria provided, single submitter	clinical testing	The TERT c.3150G>C (p.Lys1050Asn) missense variant has been identified by Collopy et al. (2015) in a homozygous state in one individual and his sister, both of whom have bone marrow failure and nail dystrophy. Both individuals also showed a shortened telomere length. The variant was shown to result in 56% of telomerase activity compared to wild type. The brother was also found to carry a heterozygous variant in the TERC gene which resulted in 4.7% telomerase activity. Control data are unavailable for the p.Lys1050Asn variant, which is reported at a frequency of 0.00047 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited. The p.Lys1050Asn variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for dyskeratosis congenita. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina	RCV000398654	SCV000452231	uncertain significance	Aplastic anemia	2017-04-28	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	RCV000309581	SCV000452232	benign	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1	2017-04-28	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.
Invitae	RCV002523498	SCV000551540	likely benign	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2024-01-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001815383	SCV000597462	uncertain significance	not specified	2020-10-15	criteria provided, single submitter	clinical testing	DNA sequence analysis of the TERT gene demonstrated a sequence change, c.3150G>C, in exon 14 that results in an amino acid change, p.Lys1050Asn. This sequence change has been reported in the gnomAD database with a frequency of 0.2% in the Ashkenazi Jewish sub-population (dbSNP rs373400596). The p.Lys1050Asn change affects a moderately conserved amino acid residue located in a domain of the TERT protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, Revel) provide contradictory results for the p.Lys1050Asn substitution. This sequence change has been described in the homozygous state in one individual with bone marrow failure, nail dystrophy, renal failure, and dental/skin abnormalities, in addition to a novel heterozygous sequence change in the TERC gene. This individual’s sister with bone marrow failure and nail dystrophy was also found to be homozygous for this TERT variant, but did not carry the same variant in TERC (PMID: 26024875). Results of other first-degree relatives from this family were not reported. The p.Lys1050Asn change has been demonstrated to reduce telomerase activity compared with normal controls, however normal telomerase cutoffs have not been well established (PMID: 26024875). A different pathogenic sequence change affecting the same amino acid residue (p.Lys1050Glu) has been described in a patient with pulmonary fibrosis (PMID: 18635888). Due to the frequency of this sequence change in population databases, the p.Lys1050Asn is classified as a variant of unknown significance.
Sema4, Sema4	RCV002255372	SCV002533147	uncertain significance	Dyskeratosis congenita	2021-06-15	criteria provided, single submitter	curation
GeneDx	RCV002509370	SCV002818798	uncertain significance	not provided	2023-01-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate intermediate telomerase activity (Collopy 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29758336, 27540018, 29463756, 26024875, 26158642, 28495916, 27354474, 29625052, 28104920, 31448843, 32526789)
Baylor Genetics	RCV000344253	SCV004203622	uncertain significance	Dyskeratosis congenita, autosomal dominant 2	2023-09-02	criteria provided, single submitter	clinical testing