VCV000050985.122 - ClinVar

NM_006087.4(TUBB4A):c.745G>A (p.Asp249Asn)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(16)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006087.4(TUBB4A):c.745G>A (p.Asp249Asn)

Variation ID: 50985 Accession: VCV000050985.122

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.3 19: 6495754 (GRCh38) [ NCBI UCSC ] 19: 6495765 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 19, 2014	Oct 20, 2024	May 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006087.4:c.745G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006078.2:p.Asp249Asn	missense
NM_001289123.2:c.898G>A	NP_001276052.1:p.Asp300Asn	missense
NM_001289127.2:c.880G>A	NP_001276056.1:p.Asp294Asn	missense
NM_001289129.2:c.745G>A	NP_001276058.1:p.Asp249Asn	missense
NM_001289130.2:c.529G>A	NP_001276059.1:p.Asp177Asn	missense
NM_001289131.2:c.529G>A	NP_001276060.1:p.Asp177Asn	missense
NC_000019.10:g.6495754C>T
NC_000019.9:g.6495765C>T
NG_033896.1:g.12095G>A
	P04350:p.Asp249Asn

... more HGVS ... less HGVS

Protein change

D249N, D300N, D177N, D294N

Other names

Canonical SPDI

NC_000019.10:6495753:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA143913 UniProtKB: P04350#VAR_069799 OMIM: 602662.0002 dbSNP: rs483352809 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TUBB4A		No evidence available	No evidence available	GRCh38 GRCh37	293	325

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hypomyelinating leukodystrophy 6	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Jan 1, 2023	RCV000043681.31
not provided	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	May 18, 2023	RCV000255689.36
Hypomyelinating leukodystrophy 6 Torsion dystonia 4	Pathogenic (1)	criteria provided, single submitter	Jan 15, 2019	RCV001249621.12
Abnormality of the nervous system	Pathogenic (1)	criteria provided, single submitter	Jul 10, 2021	RCV001814029.9

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 15, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Torsion dystonia 4 Hypomyelinating leukodystrophy 6 Affected status: yes Allele origin: germline	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV001423694.1 First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020	Comment: [ACMG/AMP: PS2, PS3, PM1, PM2, PP2, PP3] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity … (more) [ACMG/AMP: PS2, PS3, PM1, PM2, PP2, PP3] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3]. (less)
Likely pathogenic (Jul 07, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449614.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1
Pathogenic (Jul 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormality of the nervous system Affected status: yes Allele origin: germline	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV001755669.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022
Pathogenic (Jan 25, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypomyelinating leukodystrophy 6 Affected status: yes Allele origin: de novo	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002072571.1 First in ClinVar: Feb 05, 2022 Last updated: Feb 05, 2022	Comment: This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS3, PM1, PM2_SUP, PP3
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypomyelinating leukodystrophy 6 Affected status: yes Allele origin: germline	3billion Accession: SCV002521548.1 First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022	Publications: PubMed (3) PubMed: 25545912‚ 24706558‚ 23582646 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more) The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000050985). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:23582646, 24706558, 25545912). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Global developmental delay (present) , Failure to thrive (present) , Growth delay (present) , Expressive language delay (present) , Spastic tetraparesis (present) , Generalized dystonia … (more) Global developmental delay (present) , Failure to thrive (present) , Growth delay (present) , Expressive language delay (present) , Spastic tetraparesis (present) , Generalized dystonia (present) , Paroxysmal dystonia (present) , Developmental regression (present) , Involuntary movements (present) , CNS hypomyelination (present) , Hypoplasia of the corpus callosum (present) , Small basal ganglia (present) , Aplasia/Hypoplasia of the cerebellum (present) , Caudate atrophy (present) (less)
Pathogenic (Sep 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypomyelinating leukodystrophy 6 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Baylor Genetics Accession: SCV000807291.2 First in ClinVar: Oct 11, 2015 Last updated: Dec 11, 2022	Publications: PubMed (2) PubMed: 25326635‚ 23582646 Comment: This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 13-year-old male with a progressive neurological … (more) This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 13-year-old male with a progressive neurological disorder with mild intellectual disability, hypotonia at 17m (resolved), ataxia, spasticity, dystonia, possible seizures, short stature, microcephaly, hyperopia, brain abnormalities. (less)
Pathogenic (Oct 29, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypomyelinating leukodystrophy 6 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002556601.2 First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022	Publications: PubMed (2) PubMed: 23582646‚ 24785942 Comment: The TUBB4A c.745G>A missense variant is classified as PATHOGENIC (PS4_moderate, PM2, PS2, PP2, PP3) The TUBB4A c.745G>A missense variant is a single nucleotide change in … (more) The TUBB4A c.745G>A missense variant is classified as PATHOGENIC (PS4_moderate, PM2, PS2, PP2, PP3) The TUBB4A c.745G>A missense variant is a single nucleotide change in exon 4 of the TUBB4A gene, which is predicted to change the amino acid aspartic acid at position 249 in the protein to asparagine. This recurrent variant has been reported in multiple patients with leukodystrophy, specifically, hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) (PMID:23582646, PMID:24785942) (PS4_moderate). This variant is de novo in this patient and in the majority of reported cases in the literature (PS2). The variant is in dbSNP (rs483352809) but is absent from population databases (PM2). This variant has been reported in ClinVar as pathogenic by multiple other diagnostic laboratories (Variation ID:50985). The variant is a missense variant in a gene with low rate of benign missense variants (PP2). Computational predictions support a deleterious effect on the gene or gene product (PP3). (less)
Pathogenic (May 18, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000322050.9 First in ClinVar: Oct 09, 2016 Last updated: May 27, 2023	Comment: 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; … (more) 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; This variant is associated with the following publications: (PMID: 34514881, 23582646, 28973395, 30079973, 30350845, 32371413, 32463361, 7983175, 25326635, 24785942, 24706558, 24850488, 25545912, 32005694, 35586607) (less)
Pathogenic (Aug 05, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002022480.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Oct 05, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypomyelinating leukodystrophy 6 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001219584.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 28973395‚ 30079973‚ 23582646‚ 24706558‚ 25545912 Comment: Experimental studies have shown that this missense change affects TUBB4A function (PMID: 28973395, 30079973). Advanced modeling of protein sequence and biophysical properties (such as structural, … (more) Experimental studies have shown that this missense change affects TUBB4A function (PMID: 28973395, 30079973). 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 TUBB4A protein function. ClinVar contains an entry for this variant (Variation ID: 50985). This missense change has been observed in individual(s) with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) (PMID: 23582646, 24706558, 25545912). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 249 of the TUBB4A protein (p.Asp249Asn). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypomyelinating leukodystrophy 6 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV005201015.1 First in ClinVar: Sep 08, 2024 Last updated: Sep 08, 2024	Publications: PubMed (4) PubMed: 18466252‚ 23582646‚ 28973395‚ 30079973
Pathogenic (Aug 01, 2019)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248473.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
pathogenic (Dec 30, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypomyelinating leukodystrophy 6 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Molecular Diagnostics Lab, Nemours Children's Health, Delaware Accession: SCV005187395.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024	Publications: PubMed (8) PubMed: 24785942‚ 2358646‚ 16707859‚ 7983175‚ 24850488‚ 18466252‚ 30079973‚ 28973395 Comment: This missense variant (c.745G>A, p.Asp248Asn) has not been observed in population databases (gnomAD), but the change has been reported in the literature (PMID 24785942, PMID … (more) This missense variant (c.745G>A, p.Asp248Asn) has not been observed in population databases (gnomAD), but the change has been reported in the literature (PMID 24785942, PMID 23582646, PMID 16707859, PMID 7983175, PMID 24850488, PMID 18466252, PMID 30079973, PMID 28973395). Variant prediction programs suggest a deleterious effect, and this is supported in published functional studies (PMID 30079973, PMID 28973395). It has been seen in 3 unrelated affected individuals in this laboratory. (less) Observation 1: Age: 10-19 years Sex: male Tissue: blood Observation 2: Age: 0-9 years Sex: female Tissue: blood Observation 3: Sex: female Tissue: blood
Pathogenic (May 21, 2014)	no assertion criteria provided Method: literature only	LEUKODYSTROPHY, HYPOMYELINATING, 6 Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000071692.4 First in ClinVar: Jun 23, 2013 Last updated: Nov 11, 2023	Publications: PubMed (5) PubMed: 23582646‚ 18466252‚ 7983175‚ 24850488‚ 16707859 Comment on evidence: In 9 unrelated patients with hypomyelinating leukodystrophy-6 (HLD6; 612438), Simons et al. (2013) identified a de novo heterozygous c.745G-A transition in the TUBB4A gene, resulting … (more) In 9 unrelated patients with hypomyelinating leukodystrophy-6 (HLD6; 612438), Simons et al. (2013) identified a de novo heterozygous c.745G-A transition in the TUBB4A gene, resulting in an asp249-to-asn (D249N) substitution at a highly conserved residue in the T7 loop, which interacts with the GTP nucleotide bound to the N-site of the alpha-tubulin and is important for the longitudinal interaction between tubulins. Two sibs with the disorder inherited the mutation from their unaffected mother, who was found to be somatic mosaic for the mutation. The D249N mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in several large control exome databases. TUBB4A is highly expressed in neurons, and Simons et al. (2013) suggested that the mutation may result in a dominant-negative effect on tubulin dimerization, microtubule polymerization, or microtubule stability in neurons with a secondary involvement of glial cells. The phenotype was characterized primarily by onset in the first years of life of delayed motor development or gait instability, followed motor deterioration and extrapyramidal signs. Six patients had cognitive decline, 2 had mild intellectual disability, and 3 had normal cognitive development. All patients except 1 had some sort of speech delay and dysarthria. Simons et al. (2013) noted that the D249N substitution has been identified in other beta-tubulins as being pathogenic: in the Tubb1 gene (612901) in Cavalier King Charles Spaniel dogs with inherited macrothrombocytopenia (Davis et al., 2008), and in a beta-tubulin gene in C. elegans with loss of touch sensitivity (Savage et al., 1994). Miyatake et al. (2014) identified the D249N mutation in 2 unrelated Japanese patients with HLD6, 1 of whom had previously been reported by Wakusawa et al. (2006). The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or 1000 Genomes Project databases, or in 575 in-house control exomes. The mutation occurred de novo in 1 patient and was absent from the mother's DNA in the second patient; paternal DNA for the second patient was not available. The D249N substitution occurs at an intraheterodimer interface, suggesting that the mutation may affect tubulin heterodimerization; however, functional studies were not performed. (less)
not provided (-)	no classification provided Method: not provided	Leukodystrophy, hypomyelinating, 6 Affected status: not provided Allele origin: germline	Texas Scottish Rite Hospital for Children Accession: SCV000148341.1 First in ClinVar: Apr 19, 2014 Last updated: Apr 19, 2014
not provided (-)	no classification provided Method: literature only	Hypomyelinating leukodystrophy 6 Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000328453.3 First in ClinVar: Oct 11, 2015 Last updated: Oct 01, 2022	Publications: PubMed (4) PubMed: 24785942‚ 24850488‚ 23582646‚ 24706558 BookShelf: NBK395611 BookShelf: NBK395611
click to load more click to collapse

Comment:

[ACMG/AMP: PS2, PS3, PM1, PM2, PP2, PP3] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3].

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000050985). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:23582646, 24706558, 25545912). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 13-year-old male with a progressive neurological disorder with mild intellectual disability, hypotonia at 17m (resolved), ataxia, spasticity, dystonia, possible seizures, short stature, microcephaly, hyperopia, brain abnormalities.

Comment:

The TUBB4A c.745G>A missense variant is classified as PATHOGENIC (PS4_moderate, PM2, PS2, PP2, PP3) The TUBB4A c.745G>A missense variant is a single nucleotide change in exon 4 of the TUBB4A gene, which is predicted to change the amino acid aspartic acid at position 249 in the protein to asparagine. This recurrent variant has been reported in multiple patients with leukodystrophy, specifically, hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) (PMID:23582646, PMID:24785942) (PS4_moderate). This variant is de novo in this patient and in the majority of reported cases in the literature (PS2). The variant is in dbSNP (rs483352809) but is absent from population databases (PM2). This variant has been reported in ClinVar as pathogenic by multiple other diagnostic laboratories (Variation ID:50985). The variant is a missense variant in a gene with low rate of benign missense variants (PP2). Computational predictions support a deleterious effect on the gene or gene product (PP3).

Comment:

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; This variant is associated with the following publications: (PMID: 34514881, 23582646, 28973395, 30079973, 30350845, 32371413, 32463361, 7983175, 25326635, 24785942, 24706558, 24850488, 25545912, 32005694, 35586607)

Comment:

Experimental studies have shown that this missense change affects TUBB4A function (PMID: 28973395, 30079973). 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 TUBB4A protein function. ClinVar contains an entry for this variant (Variation ID: 50985). This missense change has been observed in individual(s) with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) (PMID: 23582646, 24706558, 25545912). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 249 of the TUBB4A protein (p.Asp249Asn). For these reasons, this variant has been classified as Pathogenic.

Comment:

This missense variant (c.745G>A, p.Asp248Asn) has not been observed in population databases (gnomAD), but the change has been reported in the literature (PMID 24785942, PMID 23582646, PMID 16707859, PMID 7983175, PMID 24850488, PMID 18466252, PMID 30079973, PMID 28973395). Variant prediction programs suggest a deleterious effect, and this is supported in published functional studies (PMID 30079973, PMID 28973395). It has been seen in 3 unrelated affected individuals in this laboratory.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Motor protein binding and mitochondrial transport are altered by pathogenic TUBB4A variants.	Vulinovic F	Human mutation	2018	PMID: 30079973
TUBB4A mutations result in specific neuronal and oligodendrocytic defects that closely match clinically distinct phenotypes.	Curiel J	Human molecular genetics	2017	PMID: 28973395
TUBB4A-Related Leukodystrophy.	Adam MP	-	2016	PMID: 27809427
H-ABC syndrome and DYT4: Variable expressivity or pleiotropy of TUBB4 mutations?	Erro R	Movement disorders : official journal of the Movement Disorder Society	2015	PMID: 25545912
Expanding the phenotypic spectrum of TUBB4A-associated hypomyelinating leukoencephalopathies.	Miyatake S	Neurology	2014	PMID: 24850488
Hypomyelination with atrophy of the basal ganglia and cerebellum: further delineation of the phenotype and genotype-phenotype correlation.	Hamilton EM	Brain : a journal of neurology	2014	PMID: 24785942
Novel TUBB4A mutations and expansion of the neuroimaging phenotype of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC).	Ferreira C	American journal of medical genetics. Part A	2014	PMID: 24706558
A de novo mutation in the β-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum.	Simons C	American journal of human genetics	2013	PMID: 23582646
Mutation in beta1-tubulin correlates with macrothrombocytopenia in Cavalier King Charles Spaniels.	Davis B	Journal of veterinary internal medicine	2008	PMID: 18466252
Effective treatment with levodopa and carbidopa for hypomyelination with atrophy of the basal ganglia and cerebellum.	Wakusawa K	The Tohoku journal of experimental medicine	2006	PMID: 16707859
Mutations in the Caenorhabditis elegans beta-tubulin gene mec-7: effects on microtubule assembly and stability and on tubulin autoregulation.	Savage C	Journal of cell science	1994	PMID: 7983175
Professional certification and gerontological nursing.	Futrell M	Journal of gerontological nursing	1990	PMID: 2358646
click to load more click to collapse

Text-mined citations for rs483352809 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_006087.4(TUBB4A):c.745G>A (p.Asp249Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs483352809 ...