ClinVar Miner

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

dbSNP: rs752176040
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Total submissions: 9
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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 Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1 2017-07-05 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000677638 SCV001251436 pathogenic Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1 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 2020-03-26 criteria provided, single submitter clinical testing The alteration results in a premature stop codon: The c.139_140delAG (p.S47*) alteration, located in coding exon 2 of the TMCO1 gene, results from the deletion of 2 nucleotides from position 139 to 140, causing a translational frameshift with a predicted alternate stop codon at amino acid position 47. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration is rare in population databases: Based on data from the Genome Aggregation Database (gnomAD), the c.139_140delAG alteration was observed in 0.0103% (29/282,676) of total alleles studied. No homozygotes were reported in gnomAD. The alteration has been observed in affected individuals: The c.139_140delAG (p.S47*) alteration in TMCO1 has been reported homozygous in multiple patients of different ethnicities with cerebrofaciothoracic dysplasia (Xin, 2010; Yates, 2019). Based on the available evidence, this alteration is classified as pathogenic.
Invitae RCV000481400 SCV001591696 pathogenic not provided 2023-12-19 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. Loss-of-function variants in TMCO1 are known to be pathogenic (PMID: 20018682, 23320496, 24194475, 24424126). This variant is present in population databases (rs752176040, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with craniofacial dysmorphism, skeletal anomalies, and mental retardation (PMID: 20018682). It has also been observed to segregate with disease in related individuals. This variant is also known as c.139_140delAG. ClinVar contains an entry for this variant (Variation ID: 420165). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000677638 SCV001653001 likely pathogenic Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1 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.
Fulgent Genetics, Fulgent Genetics RCV000677638 SCV002809942 pathogenic Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1 2022-02-09 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003419799 SCV004118033 pathogenic TMCO1-related condition 2023-04-25 criteria provided, single submitter clinical testing The TMCO1 c.292_293delAG variant is predicted to result in premature protein termination (p.Ser98*). This variant was reported the homozygous state in six individuals from an Old Order Amish family, all with craniofacial dysmorphism, skeletal anomalies, and intellectual disability; the variant was shown to segregate with disease within the family (variant described as c.139_140delAG, p.Ser47Ter in Xin et al. 2010. PubMed ID: 20018682). Further testing of undiagnosed children identified five additional Amish individuals with a similar phenotype, all homozygous for the c.292_293delAG (p.Ser98*) variant (Xin et al. 2010. PubMed ID: 20018682). This variant has also been reported in the homozygous state in three Pakistani brothers and one Scottish individual, all with craniofacial dysmorphism, skeletal anomalies, and intellectual disability (Yates et al. 2019. PubMed ID: 30556256). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-165737436-ACT-A). Other predicted loss-of-function variants in TMCO1 have been reported in affected individuals (Human Gene Mutation Database, https://www.hgmd.cf.ac.uk/). In summary, this variant is interpreted as pathogenic.
OMIM RCV000677638 SCV000045387 pathogenic Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1 2010-01-05 no assertion criteria provided literature only

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