Submissions for variant NM_030773.4(TUBB1):c.721C>T (p.Arg241Trp)

gnomAD frequency: 0.00011  dbSNP: rs368923302

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Johns Hopkins Genomics, Johns Hopkins University	RCV001683761	SCV001905494	uncertain significance	Macrothrombocytopenia, isolated, 1, autosomal dominant	2021-08-12	criteria provided, single submitter	clinical testing	This TUBB1 variant (rs368923302) is rare (<0.1%) in a large population dataset (gnomAD: 28/282856 total alleles; 0.01%; no homozygotes) and has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is strongly conserved across the vertebrate species assessed. This variant is not predicted to affect normal exon 4 splicing, although this has not been confirmed experimentally to our knowledge. Due to insufficient evidence, we consider the clinical significance of c.721C>T to be uncertain at this time.
Genetic Services Laboratory, University of Chicago	RCV001819968	SCV002065392	uncertain significance	not specified	2021-06-18	criteria provided, single submitter	clinical testing	DNA sequence analysis of the TUBB1 gene demonstrated a sequence change, c.721C>T, in exon 4 that results in an amino acid change, p.Arg241Trp. This sequence change has been described in gnomAD with a frequency of 0.015% in the Non-finnish European sub-population (dbSNP rs368923302). The p.Arg241Trp change affects a highly conserved amino acid residue located in a domain of the TUBB1 protein that is known to be functional. The p.Arg241Trp substitution appears to be damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in two individuals fro the same family with thrombocytopenia (PMID: 27479822). Due to the lack of sufficient evidences and functional studies, the clinical significance of the p.Arg241Trp change remains unknown at this time.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV001683761	SCV002515679	uncertain significance	Macrothrombocytopenia, isolated, 1, autosomal dominant		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002537735	SCV003443848	uncertain significance	not provided	2022-06-22	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 988864). This missense change has been observed in individual(s) with thrombocytopenia (PMID: 27479822). This variant is present in population databases (rs368923302, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 241 of the TUBB1 protein (p.Arg241Trp). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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.
Birmingham Platelet Group; University of Birmingham	RCV001270583	SCV001450882	uncertain significance	Abnormal bleeding; Thrombocytopenia	2020-05-01	no assertion criteria provided	research