Submissions for variant NM_030773.4(TUBB1):c.35del (p.Cys12fs)

gnomAD frequency: 0.00006  dbSNP: rs773248042

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002222613	SCV002500914	pathogenic	Macrothrombocytopenia, isolated, 1, autosomal dominant		criteria provided, single submitter	clinical testing
Mendelics	RCV002222613	SCV002519923	uncertain significance	Macrothrombocytopenia, isolated, 1, autosomal dominant	2023-04-12	criteria provided, single submitter	clinical testing
GeneDx	RCV002293476	SCV002586623	likely pathogenic	not provided	2024-11-14	criteria provided, single submitter	clinical testing	Frameshift 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: 29333906, 30446499, 31589614, 34662886, 34516618, 32757236, 28983057, 37647632)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002293476	SCV003271425	uncertain significance	not provided	2022-10-20	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 586966). This premature translational stop signal has been observed in individual(s) with thrombocytopenia and/or TUBB1-related macrothrombocytopenia (PMID: 28983057, 30446499, 32757236). This variant is present in population databases (rs773248042, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Cys12Leufs*12) in the TUBB1 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TUBB1 cause disease.
PreventionGenetics, part of Exact Sciences	RCV003420272	SCV004117299	uncertain significance	TUBB1-related disorder	2022-10-06	criteria provided, single submitter	clinical testing	The TUBB1 c.35delG variant is predicted to result in a frameshift and premature protein termination (p.Cys12Leufs*12). This variant has been reported in an individual with thyroid dysgenesis, and the variant was inherited from a parent with mild thyroid asymmetry but with normal thyroid function (Stoupa et al. 2018. PubMed ID: 30446499). This variant has also been reported in an individual with an inherited platelet disorder (Bastida et al. 2018. PubMed ID: 28983057) and an individual with nonsyndromic thrombocytopenia (Guéguen et al. 2020. PubMed ID: 32757236). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-57594611-TG-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222613	SCV004813279	pathogenic	Macrothrombocytopenia, isolated, 1, autosomal dominant	2024-02-14	criteria provided, single submitter	clinical testing	Variant summary: TUBB1 c.35delG (p.Cys12LeufsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.2e-05 in 251248 control chromosomes (gnomAD). c.35delG has been reported in the literature in individuals affected with congenital hypothyroidism or inherited platelet disorders (Stoupa_2018, Bastida_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34662886, 28983057, 32757236, 30446499). ClinVar contains an entry for this variant (Variation ID: 586966). Based on the evidence outlined above, the variant was classified as pathogenic.
Polak associated Lab, IMAGINE Institute	RCV000714242	SCV000840555	pathogenic	Congenital hypothyroidism	2016-10-18	no assertion criteria provided	research
Unidade de Genética Molecular, Centro Hospitalar Universitário do Porto	RCV002222613	SCV002540770	pathogenic	Macrothrombocytopenia, isolated, 1, autosomal dominant	2022-07-07	no assertion criteria provided	research	Variant identified in homozygosity in two of five affected members in the same family. PVS1, PP5, PP1
OMIM	RCV002222613	SCV004042667	pathogenic	Macrothrombocytopenia, isolated, 1, autosomal dominant	2023-10-12	no assertion criteria provided	literature only