Submissions for variant NM_001069.3(TUBB2A):c.743C>T (p.Ala248Val)

gnomAD frequency: 0.00003  dbSNP: rs2808001

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254754	SCV000321988	pathogenic	not provided	2021-10-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that this variant has a reduced rate of heterodimer incorporation into the in vitro cytoskeleton network in comparison with wild type-expressing cells (Cushion et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26934450, 24702957, 27770045, 32203252, 32571897)
NeuroMeGen, Hospital Clinico Santiago de Compostela	RCV000114959	SCV000693794	likely pathogenic	Complex cortical dysplasia with other brain malformations 5	2018-01-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000114959	SCV001137048	pathogenic	Complex cortical dysplasia with other brain malformations 5	2022-05-27	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000114959	SCV001149975	pathogenic	Complex cortical dysplasia with other brain malformations 5	2019-06-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000114959	SCV001525134	pathogenic	Complex cortical dysplasia with other brain malformations 5	2019-11-25	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000254754	SCV002011190	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000114959	SCV002759375	likely pathogenic	Complex cortical dysplasia with other brain malformations 5	2022-12-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000254754	SCV003262008	pathogenic	not provided	2024-03-28	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 248 of the TUBB2A protein (p.Ala248Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with TUBB2A-related conditions (PMID: 24702957, 27770045, 32203252, 32571897; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 127101). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TUBB2A protein function. Experimental studies have shown that this missense change affects TUBB2A function (PMID: 24702957, 29547997). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002514574	SCV003685323	uncertain significance	Inborn genetic diseases	2021-04-28	criteria provided, single submitter	clinical testing	The c.743C>T (p.A248V) alteration is located in exon 4 (coding exon 4) of the TUBB2A gene. This alteration results from a C to T substitution at nucleotide position 743, causing the alanine (A) at amino acid position 248 to be replaced by a valine (V). Based on data from the Genome Aggregation Database (gnomAD) database, the TUBB2A c.743C>T alteration was observed in 0.03% (87/252926) of total alleles studied, with a frequency of 0.37% (68/18432) in the African subpopulation; however, this data may be an unreliable mismapping artefact (Ragoussis, 2021). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000114959	SCV004810032	uncertain significance	Complex cortical dysplasia with other brain malformations 5	2024-04-04	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000114959	SCV005086144	pathogenic	Complex cortical dysplasia with other brain malformations 5	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a likely mechanism of disease in this gene and is associated with cortical dysplasia, complex, with other brain malformations 5, (MIM#615763). Functional studies have shown missense variants to cause weakened incorporation into cytoskeleton, and potentially impaired heterodimer formation indicating loss of function. However, the mutational spectrum is more suggestive of a dominant negative mechanism (PMID: 24702957). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (400 heterozygotes, 0 homozygotes). However, most of these are likely sequencing artefacts. The remaining were observed in individuals with a neurodevelopmental disorder (PMID: 33547136). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported once each as a VUS and likely benign; however, the majority of submissions are pathogenic and likely pathogenic (ClinVar). It has also been observed multiple times as de novo in individuals with simplified gyral patterning and infantile-onset epilepsy (PMID: 24702957, PMID: 32203252). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000114959	SCV000148869	pathogenic	Complex cortical dysplasia with other brain malformations 5	2014-04-03	no assertion criteria provided	literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202934	SCV000257767	likely benign	not specified	2015-04-14	flagged submission	clinical testing