Submissions for variant NM_030773.4(TUBB1):c.326G>A (p.Gly109Glu)

gnomAD frequency: 0.00092  dbSNP: rs41303899

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851596	SCV000899330	likely pathogenic	Thrombocytopenia	2019-02-01	criteria provided, single submitter	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851597	SCV000899331	uncertain significance	Macrothrombocytopenia	2019-02-01	criteria provided, single submitter	research
Baylor Genetics	RCV001334290	SCV001527091	uncertain significance	Macrothrombocytopenia, isolated, 1, autosomal dominant	2018-09-28	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. It has been reported to be statistically associated with low platelet count trait (note that study cohort is from general population) [PMID 24777453]
Labcorp Genetics (formerly Invitae), Labcorp	RCV001838132	SCV002395113	likely benign	not provided	2024-11-28	criteria provided, single submitter	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV001334290	SCV002500916	uncertain significance	Macrothrombocytopenia, isolated, 1, autosomal dominant		criteria provided, single submitter	clinical testing
Mendelics	RCV001334290	SCV002519924	pathogenic	Macrothrombocytopenia, isolated, 1, autosomal dominant	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800577	SCV002819521	likely benign	not specified	2024-10-28	criteria provided, single submitter	clinical testing	Variant summary: TUBB1 c.326G>A (p.Gly109Glu) results in a non-conservative amino acid change located in the Tubulin/FtsZ, GTPase domain (IPR003008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00087 in 251476 control chromosomes, predominantly at a frequency of 0.0017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in TUBB1 causing Autosomal Dominant Macrothrombocytopenia TUBB1-Related phenotype. c.326G>A has been reported in the literature in association studies as being associated with significantly lower mean platelet count and increased mean platelet volume (Auer_2014, Eicher_2016). Additionally, the variant was reported in a CVID patient cohort (Stuchly_2017), in a cohort of patients with platelet count disease and platelet function disease (Downes_2019), and in a cohort of patients with mild isolated nonsyndromic thrombocytopenia (Gueguen_2020). In all of these studies, the variant was reported in the heterozygous state. The variant was reported in the homozygous state in one patient with Familial Macrothrombocytopenia in which the variant was reported to segregate with disease but family data was not reported (Andres_2018). In another study, two homozygous siblings were reported with macrothrombocytopenia, while only one heterozygous carrier in the family had increased MPV (Palma-Barqueros_2021). These data indicate the variant in the heterozygous state may be associated with lower platelet count, but could result in Familial Macrothrombocytopenia in the homozygous state. However, to our knowledge there is no strong recessive gene-disease association for TUBB1. Functional studies in patient cells found that homozygous carriers lacked the marginal band, and b1-tubulin was disposed in aggregates in the cytoplasm, whereas the b1-tubulin marginal band was normal in platelets from heterozygous carriers. Additionally, although platelets from homozygous carriers displayed normal spreading, b1-tubulin formed aggregates localized in the cytoplasm instead than at the center of platelets, as observed in heterozygous carriers and controls. Quantitative RT-PCR showed a non-significant reduction in TUBB1 mRNA levels in homozygous carriers (Palma-Barqueros_2021). The following publications have been ascertained in the context of this evaluation (PMID: 31249973, 24777453, 31064749, 27346686, 32757236, 34516618, 28054583). ClinVar contains an entry for this variant (Variation ID: 626929). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003938152	SCV004755131	uncertain significance	TUBB1-related disorder	2024-01-16	no assertion criteria provided	clinical testing	The TUBB1 c.326G>A variant is predicted to result in the amino acid substitution p.Gly109Glu. This variant has been reported in patients with lower mean platelet counts and unaffected people (Auer et al. 2014. PubMed ID: 24777453; Andres et al. 2018. PubMed ID: 31249973; Downes et al. 2019. PubMed ID: 31064749. Table S3; Vuckovic et al. 2020. PubMed ID: 32888494. Table S2; Palma-Barqueros et al. 2021. PubMed ID: 34516618; Collins et al. 2021. PubMed ID: 33783834). The segregation of this variant showed that three patients with the homozygous state have low platelet counts in two unrelated families (Andres et al. 2018. PubMed ID: 31249973; Palma-Barqueros et al. 2021. PubMed ID: 34516618). However, this variant is reported in 242 heterozygotes and 0.16% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is more common than expected for a disease-causing variant. In ClinVar, this variant has conflicting interpretations of likely benign, uncertain significance and likely pathogenic. In summary, we classify this variant as uncertain significance.