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

gnomAD frequency: 0.00034  dbSNP: rs200092283

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255727	SCV000322176	pathogenic	not provided	2023-06-12	criteria provided, single submitter	clinical testing	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 (Martin Fernandez-Mayoralas et al., 2022); 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 (Scheidecker et al., 2015); This variant is associated with the following publications: (PMID: 25817018, 31847883, 32270730, 33137195, 35418825)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000255727	SCV000511344	pathogenic	not provided	2016-05-23	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000255727	SCV000860993	pathogenic	not provided	2018-04-23	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825552	SCV000966869	likely pathogenic	Autosomal recessive chorioretinopathy-microcephaly syndrome	2018-12-04	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV000170357	SCV001139564	pathogenic	Microcephaly and chorioretinopathy 3	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV000255727	SCV001372843	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000170357	SCV001522223	pathogenic	Microcephaly and chorioretinopathy 3	2020-08-04	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Laboratory of Human Genetics, Universidade de São Paulo	RCV000170357	SCV002538640	likely pathogenic	Microcephaly and chorioretinopathy 3	2022-06-27	criteria provided, single submitter	research	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.
PreventionGenetics, part of Exact Sciences	RCV003917581	SCV004744491	likely benign	TUBGCP4-related condition	2019-05-07	criteria provided, single submitter	clinical testing	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).
OMIM	RCV000170357	SCV000222766	pathogenic	Microcephaly and chorioretinopathy 3	2015-04-02	no assertion criteria provided	literature only
Genetic Services Laboratory, University of Chicago	RCV000170357	SCV002070491	pathogenic	Microcephaly and chorioretinopathy 3	2018-07-26	no assertion criteria provided	clinical testing	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).