ClinVar Genomic variation as it relates to human health

Converted during submission to Likely benign.

- 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.

See Variant Classification Assertion Criteria.

DKC1: BS1, BS2

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.

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.

BS1, BS2, BP4, BP7, PS3_supporting

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).

Converted during submission to Pathogenic.

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.