Submissions for variant NM_001363.4(DKC1):c.-142C>G

gnomAD frequency: 0.00229  dbSNP: rs199422241

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000434441	SCV000510751	likely benign	not provided	2016-10-03	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Genetic Services Laboratory, University of Chicago	RCV000503491	SCV000594370	uncertain significance	not specified	2017-04-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000434441	SCV000680520	likely benign	not provided	2024-01-23	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Baylor Genetics	RCV000032195	SCV000807596	likely benign	Dyskeratosis congenita, X-linked		criteria provided, single submitter	clinical testing
Daryl Scott Lab, Baylor College of Medicine	RCV000032195	SCV001448631	likely benign	Dyskeratosis congenita, X-linked	2023-12-08	criteria provided, single submitter	clinical testing	- This variant has been reported in individuals with dyskeratosis congenita (PMID: 11379875, 32426895), aplastic anemia (PMID: 27418648), immunodeficiency (PMID: 32166868) and in patients with osteosarcoma (PMID: 32191290). – not specific enough. - This variant has been observed in gnomADv4 with a frequency of 0.35% (715 hemizygotes, 1 homozygote). – meeting BA1. - Functional studies suggest that this variant results in shortened telomere length by flow cytometry (PMID: 32166868). This variant is found in the untranslated region (5' UTR). This promoter region (c.-143 to -c.134) contains a canonical transcription binding site of the DKC1 gene (PMID: 10592259). In vitro transcriptional activation studies show that this variant reduces the promoter activity (PMID 12137939). – PS3 but not strong enough. We now agree that this variant should be called likely benign mainly due to the most recent gnomAD v4 frequency being too high to cause disease. The criteria met is BA1, PS3_supporting.
Illumina Laboratory Services, Illumina	RCV000032195	SCV001451532	uncertain significance	Dyskeratosis congenita, X-linked	2019-05-01	criteria provided, single submitter	clinical testing	The DKC1 c.-142C>G variant occurs in the 5’ untranslated region and has been reported in two studies in which it was identified in three total hemizygotes and one heterozygous carrier (Knight et al. 2001; Keel et al. 2016). Knight et al. (2001) identified a pair of hemizygous brothers with dyskeratosis congenita who inherited the variant from their unaffected mother. A hemizygote with aplastic anemia was found by Keel et al. (2016). The variant was absent from 100 control X-chromosomes. The c.-142C>G is reported at a frequency of 0.004066 in the European (non-Finnish) population of the Genome Aggregation Database and is found in 18 hemizygotes. This allele frequency is high but may be consistent with reduced penetrance. The variant disrupts a canonical Sp1 transcription factor binding site (Knight et al. 2001) and was found to reduce promoter activity by 60% compared to Wild Type by Salowsky et al. (2002). Based on the conflicting evidence from the literature and the frequency databases, the c.-142C>G variant is classified as a variant of uncertain significance for dyskeratosis congenita.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001442049	SCV001644990	likely benign	Dyskeratosis congenita	2024-01-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001442049	SCV002535823	benign	Dyskeratosis congenita	2020-12-17	criteria provided, single submitter	curation
Ambry Genetics	RCV001442049	SCV002702776	uncertain significance	Dyskeratosis congenita	2018-09-24	criteria provided, single submitter	clinical testing	The c.-142C>G variant (also known as c.-141C>G) is located in the 5' untranslated region (5’ UTR) of the DKC1 gene. This variant results from a C to G substitution 142 bases upstream from the first translated codon. This variant has been reported in two male siblings with dyskeratosis congenita and a male with aplastic anemia (Knight SW et al. Hum. Genet., 2001 Apr;108:299-303; Keel SB et al. Haematologica, 2016 11;101:1343-1350). This variant was also identified in another individual with severe clinical features of dyskeratosis congenita, whose hematopoietic progenitor cells had reduced DKC1 expression (Bellodi C et al. Cell Rep, 2013 May;3:1493-502). An in vitro functional study found that this variant reduced promoter activity to 60% of wild type (Salowsky R et al. Gene, 2002 Jun;293:9-19). However, this variant did not co-segregate with disease in multiple males tested in our laboratory. In addition, based on data from gnomAD, the G allele has an overall frequency of approximately 0.2% (46/21778) total alleles studied, and it was detected in 16 hemizygous individuals. This nucleotide position is not well conserved in available vertebrate species on limited alignment. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004018697	SCV004113687	uncertain significance	DKC1-related disorder	2023-07-27	criteria provided, single submitter	clinical testing	The DKC1 c.-142C>G variant is located in the 5' untranslated region. This variant was reported in the hemizygous state in two brothers with dyskeratosis congenita and in the heterozygous state in their mother (referred to as c.-141C>G, Knight et al. 2001. PubMed ID: 11379875). It was also reported in a patient with aplastic anemia (Keel et al. 2016. PubMed ID: 27418648). This variant is located in a canonical transcription factor binding site and may alter proper transcription factor binding (Salowsky et al. 2002. PubMed ID: 12137939). This variant is also found in non-Finnish Europeans at a frequency of 0.4% and is found in many individuals in the hemizygous state. Given the high allele frequency of this variant, we suspect it is not a primary cause of disease, however, due to the absence of conclusive functional and genetic evidence, its significance remains uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV000434441	SCV004165995	benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	DKC1: BS1, BS2
OMIM	RCV000032195	SCV000032580	pathogenic	Dyskeratosis congenita, X-linked	2002-06-26	no assertion criteria provided	literature only
GeneReviews	RCV000032195	SCV000055785	pathologic	Dyskeratosis congenita, X-linked	2012-05-10	flagged submission	curation	Converted during submission to Pathogenic.
GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies	RCV000032195	SCV001169641	not provided	Dyskeratosis congenita, X-linked		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 01-05-2017 by GTR ID 1006. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect facilitates ClinVar submission from the Association for Creatine Deficiencies registry and does not attempt to reinterpret the variant.