ClinVar Miner

Submissions for variant NM_001363.5(DKC1):c.146C>T (p.Thr49Met) (rs121912304)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254868 SCV000321553 pathogenic not provided 2015-04-27 criteria provided, single submitter clinical testing The T49M variant has been reported previously in a male patient diagnosed with Hoyeraal-Hreidarsson syndrome (Knight et al., 1999). The T49M variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T49M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts that this substitution is probably damaging to the protein structure/function.
Invitae RCV000816060 SCV000956549 pathogenic Dyskeratosis congenita 2019-03-12 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 49 of the DKC1 protein (p.Thr49Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with dyskeratosis congenita (PMID: 11491307), and has been shown to segregate with Hoyeraal-Hreidarsson syndrome related disease in several families (PMID: 10583221, 24914498, 14648217). ClinVar contains an entry for this variant (Variation ID: 11591). Experimental studies have shown that this missense change results in substantial reduction in interaction with human telemoerase RNA (hTR) during the formation of telomerase holoenzyme complex (PMID: 19835419). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000012349 SCV000032583 pathogenic Dyskeratosis congenita, X-linked 2009-12-01 no assertion criteria provided literature only
GeneReviews RCV000012349 SCV000055786 pathologic Dyskeratosis congenita, X-linked 2012-05-10 no assertion criteria provided curation Converted during submission to Pathogenic.
UniProtKB/Swiss-Prot RCV000012349 SCV000090826 not provided Dyskeratosis congenita, X-linked no assertion provided not provided

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