ClinVar Miner

Submissions for variant NM_153704.6(TMEM67):c.1575+5G>A

dbSNP: rs1554555063
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000590124 SCV000693889 likely pathogenic Joubert syndrome 6 2017-06-26 criteria provided, single submitter research Despite not meeting strict ACMG criteria for Likely Pathogenic, we believe this is the correct classification, due to the specificity of the phenotype (PP4) as well as PM2: Absent from gnomAD (reasonable coverage, exomes 40X, genomes 30X). PM3: Observed in trans with a pathogenic variant. PP3 donor +5 position predicted to disrupt splicing.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002282247 SCV002571046 uncertain significance not specified 2022-07-15 criteria provided, single submitter clinical testing Variant summary: TMEM67 c.1575+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 5 prime splicing donor site; two predict the variant weakens a 5 prime donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 247428 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1575+5G>A in individuals affected with Joubert Syndrome And Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.

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