Submissions for variant NM_006087.4(TUBB4A):c.1228G>A (p.Glu410Lys)

dbSNP: rs587777428

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000122736	SCV000680419	pathogenic	Hypomyelinating leukodystrophy 6	2017-12-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763442	SCV000894209	likely pathogenic	Torsion dystonia 4; Hypomyelinating leukodystrophy 6	2021-12-21	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV000122736	SCV001449492	pathogenic	Hypomyelinating leukodystrophy 6	2020-02-03	criteria provided, single submitter	clinical testing
Neurogenetics Research Program, University of Adelaide	RCV001795219	SCV001737581	pathogenic	Cerebral palsy	2021-06-10	criteria provided, single submitter	research	Previously reported pathogenic variant (PMID: 24526230).
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000122736	SCV001775541	likely pathogenic	Hypomyelinating leukodystrophy 6		criteria provided, single submitter	clinical testing
GeneDx	RCV001563545	SCV001786509	pathogenic	not provided	2022-07-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate disturbed binding of TUBB4A to KIF1A resulting in impaired synaptic vesicle precursors (Xiao et al., 2022); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34758253, 18851904, 24850488, 24526230, 35668344, 34514881, 34531397, 33098801)
3billion	RCV000122736	SCV002012086	pathogenic	Hypomyelinating leukodystrophy 6	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported at least twice as de novoo in similarly affected indivisual (PMID: 24850488, 24526230 PS2, PS4_M). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.946, 3Cnet: 0.912, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Human Genetics Bochum, Ruhr University Bochum	RCV002463648	SCV002758635	likely pathogenic	Global developmental delay	2022-04-21	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PS4_MOD, PM6, PM2_SUP, PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122736	SCV003514793	pathogenic	Hypomyelinating leukodystrophy 6	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 410 of the TUBB4A protein (p.Glu410Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hypomyelinating leukodystrophy (PMID: 24526230, 24850488). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 135658). 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 TUBB4A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TUBB4A function (PMID: 28275661). For these reasons, this variant has been classified as Pathogenic.
Lifecell International Pvt. Ltd	RCV000122736	SCV003841252	pathogenic	Hypomyelinating leukodystrophy 6		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.1228G>A in Exon 4 of the TUBB4A gene that results in the amino acid substitution p.Glu410Lys was identified. The observed variant has a minor allele frequency of 0% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. This variant lies in the C-terminal domain of the protein. ClinVar has also classified this variant as Pathogenic/Likely Pathogenic (variant ID: 135658). This variant has previously been reported in patients for hypomyelinating leukoencephalopathies by Miyatake S, et, al., 2014. The E410K mutation, can cause a disruption in the cationic binding site and subsequently misassembled microtubules (Blumkin L, et, al., 2014). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
OMIM	RCV000122736	SCV000165990	pathogenic	Hypomyelinating leukodystrophy 6	2014-05-21	no assertion criteria provided	literature only
GeneReviews	RCV000122736	SCV000328455	not provided	Hypomyelinating leukodystrophy 6		no assertion provided	literature only
Genomics England Pilot Project, Genomics England	RCV001542616	SCV001760459	likely pathogenic	Torsion dystonia 4		no assertion criteria provided	clinical testing