VCV000190123.35 - ClinVar

NM_014444.5(TUBGCP4):c.1746G>T (p.Leu582=)

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.

(12)

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_014444.5(TUBGCP4):c.1746G>T (p.Leu582=)

Variation ID: 190123 Accession: VCV000190123.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q15.3 15: 43403697 (GRCh38) [ NCBI UCSC ] 15: 43695895 (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	May 9, 2015	Oct 8, 2024	Apr 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001141980.3:c.*3686C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		3 prime UTR
NM_014444.5:c.1746G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055259.2:p.Leu582=	synonymous
NM_001141979.3:c.*3686C>A		3 prime UTR
NM_001286414.3:c.1749G>T	NP_001273343.1:p.Leu583=	synonymous
NM_001355001.2:c.*3686C>A		3 prime UTR
NM_001411050.1:c.*3686C>A		3 prime UTR
NM_005657.4:c.*3686C>A		3 prime UTR
NC_000015.10:g.43403697G>T
NC_000015.9:g.43695895G>T
NG_042168.1:g.37639G>T
NG_042168.2:g.37598G>T

... more HGVS ... less HGVS

Protein change

Other names

p.Leu582Leu
1746G-T

Canonical SPDI

NC_000015.10:43403696:G: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.

0.00020 (T)

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

The Genome Aggregation Database (gnomAD), exomes 0.00030

1000 Genomes Project 30x 0.00031

The Genome Aggregation Database (gnomAD) 0.00034

Trans-Omics for Precision Medicine (TOPMed) 0.00043

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00050

1000 Genomes Project 0.00020

Exome Aggregation Consortium (ExAC) 0.00022

Links

ClinGen: CA199567 OMIM: 609610.0001 dbSNP: rs200092283 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.
TP53BP1		-	-	GRCh38 GRCh37	103	199
TUBGCP4		-	-	GRCh38 GRCh37	422	526

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.
Microcephaly and chorioretinopathy 3	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jul 17, 2023	RCV000170357.16
Autosomal recessive chorioretinopathy-microcephaly syndrome	Likely pathogenic (1)	criteria provided, single submitter	Dec 4, 2018	RCV000825552.5
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Apr 30, 2024	RCV000255727.21
TUBGCP4-related disorder	Likely benign (1)	no assertion criteria provided	May 7, 2019	RCV003917581.2

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 (Aug 04, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Microcephaly and chorioretinopathy 3 Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001522223.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Jan 25, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001372843.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 25817018 Comment: This sequence change affects codon 583 of the TUBGCP4 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more) This sequence change affects codon 583 of the TUBGCP4 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TUBGCP4 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs200092283, gnomAD 0.05%). This variant has been observed in individual(s) with microcephaly and chorioretinal dysplasia (PMID: 25817018). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190123). Studies have shown that this variant results in skipping of exon 16, but is expected to preserve the integrity of the reading-frame (PMID: 25817018). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 23, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000511344.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
Pathogenic (Apr 23, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000860993.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TUBGCP4 Number of individuals with the variant: 2 Sex: mixed
Likely pathogenic (Dec 04, 2018)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Autosomal recessive chorioretinopathy-microcephaly syndrome (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000966869.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Publications: PubMed (1) PubMed: 25817018 Comment: The p.Leu582Leu variant in TUBGCP4 has been reported in the compound heterozygou s state (with loss of function variants) in 3 individuals with microcephaly with … (more) The p.Leu582Leu variant in TUBGCP4 has been reported in the compound heterozygou s state (with loss of function variants) in 3 individuals with microcephaly with chorioretinopathy and segregated with disease in 1 affected relative (Scheideck er 2015). It has also been identified in 0.05% (66/128464) of European chromosom es by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 190123). In vitro functional studies support a splicing impact af fecting protein function (Scheidecker 2015). In summary, although additional stu dies are required to fully establish its clinical significance, this variant mee ts criteria to be classified as likely pathogenic for autosomal recessive microc ephaly with chorioretinopathy. ACMG/AMP Criteria applied: PM3_Strong, PP1, PS3_S upporting. (less) Number of individuals with the variant: 1
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Microcephaly and chorioretinopathy 3 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001139564.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely pathogenic (Jun 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Microcephaly and chorioretinopathy 3 Affected status: yes Allele origin: unknown	Laboratory of Human Genetics, Universidade de São Paulo Accession: SCV002538640.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022	Comment: This variant meets our criteria to be classified as pathogenic based upon segregation studies, low frequency in control samples, and in-silico evaluation of pathogenicity. Clinical Features: Microcephaly (present) Sex: male
Pathogenic (Apr 30, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000322176.12 First in ClinVar: Oct 10, 2016 Last updated: Jul 23, 2024	Comment: Reported in the homozygous state in a proband with an atypical phenotype of autism spectrum disorder and ectasia of the optic nerve sheaths with a … (more) Reported in the homozygous state in a proband with an atypical phenotype of autism spectrum disorder and ectasia of the optic nerve sheaths with a normal head circumference and no retinal anomalies (PMID: 35418825); Functional studies using fibroblasts from a patient suggest that the c.1746 G>T variant resulted in skipping of exon 16, which led to a reduction of the protein product, abnormal microtubule organization, and altered cell morphology (PMID: 25817018); This variant is associated with the following publications: (PMID: 25817018, 31847883, 32270730, 33137195, 31964843, 35418825) (less)
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Microcephaly and chorioretinopathy 3 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086148.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (2) PubMed: 25817018‚ 35418825 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microcephaly and chorioretinopathy, 3, (MIM#616335). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-PCR of cDNA derived from an affected individual's fibroblasts has demonstrated this variant causes inframe exon 16 skipping, but also the retention of wildtype protein. The proportion of wildtype and mutant protein is unclear (PMID: 25817018). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (86 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated Gamma tubulin complex component C-terminal domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as likely pathogenic or pathogenic, and is a recurring variant observed in compound heterozygous individuals with microcephaly, chorioretinopathy and intellectual disability (ClinVar, PMID: 25817018), and a homozygous individual with autism and ectasia of the optic nerve sheaths with no microcephaly or chorioretinopathy (PMID: 35418825). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Apr 02, 2015)	no assertion criteria provided Method: literature only	MICROCEPHALY AND CHORIORETINOPATHY, AUTOSOMAL RECESSIVE, 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000222766.1 First in ClinVar: May 09, 2015 Last updated: May 09, 2015	Publications: PubMed (1) PubMed: 25817018 Comment on evidence: In 4 French children from 3 unrelated families with autosomal recessive microcephaly and chorioretinopathy-3 (MCCRP3; 616335), Scheidecker et al. (2015) identified a synonymous c.1746G-T transversion … (more) In 4 French children from 3 unrelated families with autosomal recessive microcephaly and chorioretinopathy-3 (MCCRP3; 616335), Scheidecker et al. (2015) identified a synonymous c.1746G-T transversion (c.1746G-T, NM_014444.2) in exon 16 of the TUBGCP4 gene in compound heterozygosity. The other TUBGCP4 allele carried a c.579dupT (609610.0002), deletion of exons 16-18 (609610.0003), or c.298delT (609610.0004). The c.1746G-T transversion was predicted to act as a strongly activated cryptic acceptor splice site, resulting in the skipping of exon 16 and generation of an unstable mRNA, as demonstrated in patient cells. Mutations in the first 2 families were found by exome sequencing; mutations in the third family were found by Sanger sequencing of 12 additional French patients with a similar disorder. The c.1746G-T mutation was found at a frequency of 0.00036 in the Exome Variant Server and Exome Aggregation Consortium databases. Skin fibroblasts from 1 patient showed a reduction of TUBGCP4 protein to about 40% of control values; the protein was decreased in the centrosomes, both in interphase and during mitosis. Levels of all other components of the gamma-tubulin complex were also decreased. (less)
Pathogenic (Jul 26, 2018)	no assertion criteria provided Method: clinical testing	Microcephaly and chorioretinopathy 3 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002070491.3 First in ClinVar: Jan 29, 2022 Last updated: Dec 11, 2022	Comment: DNA sequence analysis of the TUBGCP4 gene demonstrated a synonymous pathogenic sequence change, c.1746G>T p. Leu582Leu, in exon 16, that does not result in an … (more) DNA sequence analysis of the TUBGCP4 gene demonstrated a synonymous pathogenic sequence change, c.1746G>T p. Leu582Leu, in exon 16, that does not result in an amino acid substitution. This silent sequence change was previously reported in in the compound heterozygous state in a patient with TUBGCP4-related microcephaly and chorioretinopathy (PMID: 25817018). Functional analysis of individual fibroblasts demonstrated that the c.1746G>T variant resulted in skipping of exon 16, which led to a reduction of the protein product (PMID: 25817018). (less)
Likely benign (May 07, 2019)	no assertion criteria provided Method: clinical testing	TUBGCP4-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004744491.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Comment:

This sequence change affects codon 583 of the TUBGCP4 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TUBGCP4 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs200092283, gnomAD 0.05%). This variant has been observed in individual(s) with microcephaly and chorioretinal dysplasia (PMID: 25817018). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190123). Studies have shown that this variant results in skipping of exon 16, but is expected to preserve the integrity of the reading-frame (PMID: 25817018). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.Leu582Leu variant in TUBGCP4 has been reported in the compound heterozygou s state (with loss of function variants) in 3 individuals with microcephaly with chorioretinopathy and segregated with disease in 1 affected relative (Scheideck er 2015). It has also been identified in 0.05% (66/128464) of European chromosom es by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 190123). In vitro functional studies support a splicing impact af fecting protein function (Scheidecker 2015). In summary, although additional stu dies are required to fully establish its clinical significance, this variant mee ts criteria to be classified as likely pathogenic for autosomal recessive microc ephaly with chorioretinopathy. ACMG/AMP Criteria applied: PM3_Strong, PP1, PS3_S upporting.

Comment:

Reported in the homozygous state in a proband with an atypical phenotype of autism spectrum disorder and ectasia of the optic nerve sheaths with a normal head circumference and no retinal anomalies (PMID: 35418825); Functional studies using fibroblasts from a patient suggest that the c.1746 G>T variant resulted in skipping of exon 16, which led to a reduction of the protein product, abnormal microtubule organization, and altered cell morphology (PMID: 25817018); This variant is associated with the following publications: (PMID: 25817018, 31847883, 32270730, 33137195, 31964843, 35418825)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microcephaly and chorioretinopathy, 3, (MIM#616335). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-PCR of cDNA derived from an affected individual's fibroblasts has demonstrated this variant causes inframe exon 16 skipping, but also the retention of wildtype protein. The proportion of wildtype and mutant protein is unclear (PMID: 25817018). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (86 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated Gamma tubulin complex component C-terminal domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as likely pathogenic or pathogenic, and is a recurring variant observed in compound heterozygous individuals with microcephaly, chorioretinopathy and intellectual disability (ClinVar, PMID: 25817018), and a homozygous individual with autism and ectasia of the optic nerve sheaths with no microcephaly or chorioretinopathy (PMID: 35418825). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

DNA sequence analysis of the TUBGCP4 gene demonstrated a synonymous pathogenic sequence change, c.1746G>T p. Leu582Leu, in exon 16, that does not result in an amino acid substitution. This silent sequence change was previously reported in in the compound heterozygous state in a patient with TUBGCP4-related microcephaly and chorioretinopathy (PMID: 25817018). Functional analysis of individual fibroblasts demonstrated that the c.1746G>T variant resulted in skipping of exon 16, which led to a reduction of the protein product (PMID: 25817018).

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
Bi-Allelic c.1746G>T; p.Leu582= Variants in TUBGCP4 in a Boy with Autism: Clinical Data and Literature Review.	Martín Fernández-Mayoralas D	Molecular syndromology	2022	PMID: 35418825
Mutations in TUBGCP4 alter microtubule organization via the γ-tubulin ring complex in autosomal-recessive microcephaly with chorioretinopathy.	Scheidecker S	American journal of human genetics	2015	PMID: 25817018
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TUBGCP4	-	-	-	-

Text-mined citations for rs200092283 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_014444.5(TUBGCP4):c.1746G>T (p.Leu582=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs200092283 ...