Submissions for variant NM_001069.3(TUBB2A):c.1172G>A (p.Arg391His)

dbSNP: rs1057521250

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000434280	SCV000521886	pathogenic	not provided	2024-10-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 33547136)
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000434280	SCV001334427	likely pathogenic	not provided	2019-12-12	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198834	SCV001369829	uncertain significance	Complex cortical dysplasia with other brain malformations 5	2019-03-08	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PP3,PP5.
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli	RCV001420214	SCV001622634	likely pathogenic	See cases	2021-04-26	criteria provided, single submitter	clinical testing	PM2_supporting;PM6_moderate;PP2_supporting;PP3_supporting
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001420214	SCV002523548	uncertain significance	See cases	2020-02-03	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4, PM2, PP2, PP3
NYU Undiagnosed Diseases Program, NYU School of Medicine	RCV001198834	SCV002526448	likely pathogenic	Complex cortical dysplasia with other brain malformations 5	2022-06-21	criteria provided, single submitter	research	This variant is absent in the Genome Aggregation Database (gnomADv2 & v3), indicating it is not a common benign variant in the populations represented in this database. This exact variant was reported as a de novo heterozygous change in one individual with intellectual disability in the 100,000 Genomes Project (PMID: 33547136). This variant is in the ClinVar database as having conflicting interpretations of pathogenicity, with three laboratories classifying it as likely pathogenic and one as a variant of uncertain clinical significance (Variation ID: 369087, last accessed on 4/25/2022). se variation is a known mechanism of disease in the TUBB2A gene (PMIDs: 33776625, 32571897). Additionally, this gene has a low rate of benign missense variation on gnomADv2 (Z=5.26). Multiple in silico programs show largely consistent predictions for altering the protein structure and/or function, supporting the pathogenicity of this variant (Pathogenic, REVEL score: 0.85, Damaging, PROVEAN score: -2.52). This same amino acid change (p.Arg391His) along with p.Arg391Cys have been previously documented as pathogenic variants in a different tubulin-family gene, TUBB4B, associated with a different disease (Leber congenital amaurosis) (Pubmed ID: 29198720). p.Arg391 is located in the H11 helix of -tubulin which forms a binding pocket that interacts with -tubulin. The substitutions at p.Arg391 in TUBB4B are predicted to cause conformational changes to this binding pocket, and functional studies showed these substitutions caused abnormal microtubule growth. TUBB4B is highly homologous to TUBB2A, and therefore, this data is supportive of pathogenicity of p.Arg391His in TUBB2A.