Submissions for variant NM_001069.3(TUBB2A):c.872A>C (p.Gln291Pro)

dbSNP: rs863224939

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UCLA Clinical Genomics Center, UCLA	RCV000195901	SCV000255499	likely pathogenic	Complex cortical dysplasia with other brain malformations 5	2014-01-28	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000195901	SCV002512281	likely pathogenic	Complex cortical dysplasia with other brain malformations 5	2022-02-10	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 supporting, PM2 moderate, PM6, PP3 supporting
GeneDx	RCV002264917	SCV002546687	likely pathogenic	not provided	2022-07-02	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28840640, 32203252, 31589614, 25326637)
Invitae	RCV002264917	SCV003483365	uncertain significance	not provided	2022-03-23	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TUBB2A protein function. ClinVar contains an entry for this variant (Variation ID: 217024). This missense change has been observed in individual(s) with TUBB2A-related conditions (PMID: 25326637). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 291 of the TUBB2A protein (p.Gln291Pro).
PreventionGenetics, part of Exact Sciences	RCV003897431	SCV004709827	uncertain significance	TUBB2A-related condition	2023-12-12	criteria provided, single submitter	clinical testing	The TUBB2A c.872A>C variant is predicted to result in the amino acid substitution p.Gln291Pro. This variant was reported to have occurred de novo in an individual with developmental delay, short stature, seizures, ureteropelvic junction obstruction, constipation, hydronephrosis, clinodactyly, growth hormone deficiency, and Russell Silver syndrome (Lee et al. 2014. PubMed ID: 25326637, eTable 2). This variant was also reported in a presumably unaffected gamete donor in a large carrier screening study (Capalbo A et al 2019. PubMed ID: 31589614, supplemental table S1). At PreventionGenetics, we detected this variant in an individual with a neurodevelopmental phenotype, but it was inherited from a presumably unaffected parent (internal data). This variant has not been reported in a large population database, indicating it is rare. Although we suspect this variant may be pathogenic, at this time the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.
Diagnostic Laboratory, Strasbourg University Hospital	RCV002274940	SCV002562772	uncertain significance	Seizure		no assertion criteria provided	clinical testing