VCV000209201.2 - ClinVar

NM_006087.4(TUBB4A):c.1164G>C (p.Met388Ile)

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.

(2)

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.1164G>C (p.Met388Ile)

Variation ID: 209201 Accession: VCV000209201.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.3 19: 6495335 (GRCh38) [ NCBI UCSC ] 19: 6495346 (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	Sep 29, 2015	Feb 14, 2024	Jun 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006087.4:c.1164G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006078.2:p.Met388Ile	missense
NM_001289123.2:c.1317G>C	NP_001276052.1:p.Met439Ile	missense
NM_001289127.2:c.1299G>C	NP_001276056.1:p.Met433Ile	missense
NM_001289129.2:c.1164G>C	NP_001276058.1:p.Met388Ile	missense
NM_001289130.2:c.948G>C	NP_001276059.1:p.Met316Ile	missense
NM_001289131.2:c.948G>C	NP_001276060.1:p.Met316Ile	missense
NC_000019.10:g.6495335C>G
NC_000019.9:g.6495346C>G
NG_033896.1:g.12514G>C

... more HGVS ... less HGVS

Protein change

M388I, M439I, M316I, M433I

Other names

Canonical SPDI

NC_000019.10:6495334:C:G

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: CA250401 dbSNP: rs797045074 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	294	326

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/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 20, 2023	RCV000191139.3

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.
Likely pathogenic (Nov 05, 2014)	criteria provided, single submitter (Yang et al. 2013) Method: clinical testing	Leukodystrophy, hypomyelinating, 6 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Baylor Genetics Study: Adult_WES Accession: SCV000245548.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015	Publications: PubMed (1) PubMed: 26633545 Comment: Likely pathogenicity based on finding it once in our laboratory de novo in a 22-year-old female with spastic paraplegia, epilepsy, hyperreflexia, absent speech, severe cognitive … (more) Likely pathogenicity based on finding it once in our laboratory de novo in a 22-year-old female with spastic paraplegia, epilepsy, hyperreflexia, absent speech, severe cognitive delays, severe scoliosis, leukodystrophy, ventriculomegaly, microcephaly, osteoporosis, hip dislocation. (less) Number of individuals with the variant: 1 Age: 20-29 years Sex: female Ethnicity/Population group: Causasians
Pathogenic (Jun 20, 2023)	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: SCV004259650.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 24785942‚ 32581362‚ 33597727 Comment: 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) … (more) 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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 209201). This missense change has been observed in individual(s) with hypomyelinating leukodystrophy (PMID: 24785942, 32581362, 33597727). 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 methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 388 of the TUBB4A protein (p.Met388Ile). (less)

Comment:

Likely pathogenicity based on finding it once in our laboratory de novo in a 22-year-old female with spastic paraplegia, epilepsy, hyperreflexia, absent speech, severe cognitive delays, severe scoliosis, leukodystrophy, ventriculomegaly, microcephaly, osteoporosis, hip dislocation.

Comment:

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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 209201). This missense change has been observed in individual(s) with hypomyelinating leukodystrophy (PMID: 24785942, 32581362, 33597727). 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 methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 388 of the TUBB4A protein (p.Met388Ile).

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
Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing.	Yan H	Journal of human genetics	2021	PMID: 33597727
Whole-genome sequencing of patients with rare diseases in a national health system.	Turro E	Nature	2020	PMID: 32581362
Molecular diagnostic experience of whole-exome sequencing in adult patients.	Posey JE	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26633545
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

Text-mined citations for rs797045074 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_006087.4(TUBB4A):c.1164G>C (p.Met388Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs797045074 ...