ClinVar Miner

Submissions for variant NM_000356.4(TCOF1):c.4133_4137AAGAA[1] (p.Lys1380fs) (rs587776582)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000598830 SCV000709853 pathogenic not provided 2017-10-18 criteria provided, single submitter clinical testing The c.4369_4373delAAGAA pathogenic variant in the TCOF1 gene has been reported previously (as c.4135delGAAAA) in association with Treacher Collins Syndrome (Edwards et al., 1997) and observed as a de novo variant at GeneDx. The c.4369_4373delAAGAA variant is not observed in large population cohorts (Lek et al., 2016). The deletion causes a frameshift starting with codon Lysine 1457, changes this amino acid to a Glutamic acid residue and creates a premature Stop codon at position 12 of the new reading frame, denoted p.Lys1457GlufsX12. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation. Specifically, the last 32 correct amino acids are lost and replaced by 11 incorrect amino acids.
Genetic Services Laboratory, University of Chicago RCV000004169 SCV000597428 pathogenic Treacher Collins syndrome 1 2017-02-16 criteria provided, single submitter clinical testing
Invitae RCV000004169 SCV000776781 pathogenic Treacher Collins syndrome 1 2017-10-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys1457Glufs*12) in the TCOF1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals and families affected with Treacher Collins syndrome (PMID: 9042910, 20003452, 22317976, 21951868, 11013442). ClinVar contains an entry for this variant (Variation ID: 3963). This variant has also been reported as c.4135delGAAAA and c.4366_4370delGAAAA. Loss-of-function variants in TCOF1 are known to be pathogenic (PMID: 8894686, 22317976). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004169 SCV000024335 pathogenic Treacher Collins syndrome 1 2000-10-01 no assertion criteria provided literature only

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