Submissions for variant NM_020461.4(TUBGCP6):c.2066-6A>G

gnomAD frequency: 0.00003  dbSNP: rs368765755

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000503770	SCV000597772	uncertain significance	not specified	2016-11-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000766995	SCV000680586	pathogenic	not provided	2025-03-16	criteria provided, single submitter	clinical testing	Observed with a second TUBGCP6 variant, phase unknown, in two siblings with familial exudative vitreoretinopathy and microcephaly in published literature (PMID: 31077665); Published functional studies demonstrate a damaging effect secondary to a truncated protein (PMID: 31077665); Not observed at significant frequency in large population cohorts (gnomAD); Located in a region that tolerates variation and lacks pathogenic variants; This variant is associated with the following publications: (PMID: 36307859, 37229200, 33458610, 37031378, 31077665)
Fulgent Genetics, Fulgent Genetics	RCV000765655	SCV000896985	uncertain significance	Microcephaly and chorioretinopathy 1	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000766995	SCV001249566	pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000766995	SCV001493483	pathogenic	not provided	2024-11-12	criteria provided, single submitter	clinical testing	This sequence change falls in intron 11 of the TUBGCP6 gene. It does not directly change the encoded amino acid sequence of the TUBGCP6 protein. This variant is present in population databases (rs368765755, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of microcephaly and chorioretinopathy (PMID: 31077665, 36307859, 37031378). 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: 437169). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000765655	SCV004101356	likely pathogenic	Microcephaly and chorioretinopathy 1	2023-06-07	criteria provided, single submitter	clinical testing	The TUBGCP c.2066-6A>G variant occurs in a splice region. This variant has been reported in individuals with clinical features consistent with microcephaly and chorioretinopathy, including in one individual in whom it was confirmed in trans with a likely pathogenic variant in the gene. The c.2066-6A>G variant was shown to segregate with disease in one family in two siblings (PMID: 31077665; 37031378). The highest frequency of this variant in the Genome Aggregation Database is 0.000241 in the African/African American population (version 3.1.2). Functional studies demonstrated that the c.2066-6A>G variant results in the insertion of five intronic nucleotides, which is predicted to lead to a frameshift in the protein reading frame and premature termination of the protein (PMID: 31077665). The c.2066-6A>G variant was identified in trans with a likely pathogenic variant. Based on the available evidence, the c.2066-6A>G variant is classified as likely pathogenic for microcephaly and chorioretinopathy.