ClinVar Miner

Submissions for variant NM_019026.6(TMCO1):c.139_140del (p.Gln46_Ser47insTer)

dbSNP: rs752176040
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481400 SCV000568828 pathogenic not provided 2022-05-25 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31028937, 20018682, 31102500, 30556256)
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000677638 SCV000803768 pathogenic Cerebrofaciothoracic dysplasia 2017-07-05 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000677638 SCV001251436 pathogenic Cerebrofaciothoracic dysplasia 2019-10-22 criteria provided, single submitter clinical testing The variant was confirmed as compound heterozygous with a variant of uncertain significance (NM_019026.4: c.197C>T).
Ambry Genetics RCV001266610 SCV001444786 pathogenic Inborn genetic diseases 2020-03-05 criteria provided, single submitter clinical testing
Invitae RCV000481400 SCV001591696 pathogenic not provided 2020-04-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser98*) in the TMCO1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs752176040, ExAC 0.02%). This variant has been reported to segregate with craniofacial dysmorphism, skeletal anomalies, and mental retardation in a family (PMID: 20018682). This variant is also known as c.139_140delAG in the literature. ClinVar contains an entry for this variant (Variation ID: 420165). Loss-of-function variants in TMCO1 are known to be pathogenic (PMID: 20018682, 23320496, 24194475, 24424126). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000677638 SCV001653001 likely pathogenic Cerebrofaciothoracic dysplasia 2020-06-19 criteria provided, single submitter clinical testing The c.292_293delAG (p.Ser98X) variant in TMCO1 has been reported (as c.139_140delAG: p.Ser47Ter) in the homozygous state in at least 5 individuals of Amish ancestry and in 2 additional unrelated individuals with Cerebro-facio-thoracic dysplasia, and segregated with disease in 2 affected members from 1 family (Xin 2010 PMID:20018682, Yates 2018 PMID:30556256). It has also been reported in ClinVar (Variation ID 420165). It has been identified in 0.02 (21/129086) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant creates a premature termination codon at position 98, which is predicted to lead to a truncated or absent protein. Loss of function of the TMCO1 gene is associated with autosomal recessive cerebro-facio-thoracic dysplasia. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive cerebro-facio-thoracic dysplasia. ACMG/AMP Criteria applied: PM2, PVS1_Moderate, PP1, PM3_Strong.
OMIM RCV000677638 SCV000045387 pathogenic Cerebrofaciothoracic dysplasia 2010-01-05 no assertion criteria provided literature only

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