Submissions for variant NM_153704.6(TMEM67):c.406+4A>G

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002958084	SCV003272766	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change falls in intron 3 of the TMEM67 gene. It does not directly change the encoded amino acid sequence of the TMEM67 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with TMEM67-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005239557	SCV005883506	uncertain significance	not specified	2024-12-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004733549	SCV005355797	uncertain significance	TMEM67-related disorder	2024-09-04	no assertion criteria provided	clinical testing	The TMEM67 c.406+4A>G variant is predicted to interfere with splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.