ClinVar Genomic variation as it relates to human health

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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.

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.

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.

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)

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

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).

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).