Submissions for variant NM_153704.6(TMEM67):c.651+2T>G

gnomAD frequency: 0.00003  dbSNP: rs199821258

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV000050199	SCV001428601	uncertain significance	Meckel syndrome, type 3	2017-04-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001698938	SCV002016911	likely pathogenic	not provided	2021-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851545	SCV002212325	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 6 of the TMEM67 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TMEM67 are known to be pathogenic (PMID: 20232449, 23559409). This variant is present in population databases (rs199821258, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with Joubert syndrome (PMID: 17160906). ClinVar contains an entry for this variant (Variation ID: 1373). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281687	SCV002571047	likely pathogenic	Joubert syndrome and related disorders	2022-07-18	criteria provided, single submitter	clinical testing	Variant summary: TMEM67 c.651+2T>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.6e-05 in 251174 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in TMEM67 causing Joubert Syndrome and Related Disorders (0.0018), allowing no conclusion about variant significance. c.651+2T>G has been reported in the literature in individuals affected with Joubert Syndrome and Meckel syndrome (Baala_2007 and Khaddour_2007). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1), likely pathogenic (n=1) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM	RCV000001439	SCV000021589	pathogenic	Joubert syndrome 6	2007-01-01	no assertion criteria provided	literature only
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050199	SCV000082609	probable-pathogenic	Meckel syndrome, type 3		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Clinical Genetics, Academic Medical Center	RCV001698938	SCV001925744	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001698938	SCV001963130	pathogenic	not provided		no assertion criteria provided	clinical testing