NM_014444.5(TUBGCP4):c.1746G>T (p.Leu582=) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Apr 30, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000255727.21

Allele description [Variation Report for NM_014444.5(TUBGCP4):c.1746G>T (p.Leu582=)]

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

Genes:

TUBGCP4:tubulin gamma complex component 4 [Gene - OMIM - HGNC]
TP53BP1:tumor protein p53 binding protein 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q15.3

Genomic location:

Preferred name:

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

Other names:

p.Leu582Leu

HGVS:

NC_000015.10:g.43403697G>T
NG_042168.1:g.37639G>T
NG_042168.2:g.37598G>T
NM_001141979.3:c.*3686C>A
NM_001141980.3:c.*3686C>AMANE SELECT
NM_001286414.3:c.1749G>T
NM_001355001.2:c.*3686C>A
NM_001411050.1:c.*3686C>A
NM_005657.4:c.*3686C>A
NM_014444.5:c.1746G>TMANE SELECT
NP_001273343.1:p.Leu583=
NP_055259.2:p.Leu582=
NC_000015.9:g.43695895G>T
NM_001286414.2:c.1749G>T
NM_014444.2:c.1746G>T
NM_014444.3:c.1746G>T
NM_014444.4:c.1746G>T

Nucleotide change:

1746G-T

Links:

OMIM: 609610.0001; dbSNP: rs200092283

NCBI 1000 Genomes Browser:

rs200092283

Molecular consequence:

NM_001141979.3:c.*3686C>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001141980.3:c.*3686C>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001355001.2:c.*3686C>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001411050.1:c.*3686C>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_005657.4:c.*3686C>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001286414.3:c.1749G>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_014444.5:c.1746G>T - synonymous variant - [Sequence Ontology: SO:0001819]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000322176	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 30, 2024)	germline	clinical testing	Citation Link,
SCV000511344	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 23, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000860993	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Pathogenic (Apr 23, 2018)	germline	clinical testing	Citation Link,
SCV001372843	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25817018, 28492532

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Mutations in TUBGCP4 alter microtubule organization via the γ-tubulin ring complex in autosomal-recessive microcephaly with chorioretinopathy.

Scheidecker S, Etard C, Haren L, Stoetzel C, Hull S, Arno G, Plagnol V, Drunat S, Passemard S, Toutain A, Obringer C, Koob M, Geoffroy V, Marion V, Strähle U, Ostergaard P, Verloes A, Merdes A, Moore AT, Dollfus H.

Am J Hum Genet. 2015 Apr 2;96(4):666-74. doi: 10.1016/j.ajhg.2015.02.011. Epub 2015 Mar 26.

PubMed [citation]

PMID:: 25817018
PMCID:: PMC4385181

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000322176.12

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000511344.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	0.000811	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000860993.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		2	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001372843.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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