Submissions for variant NM_001044385.3(TMEM237):c.553+1G>A

gnomAD frequency: 0.00002  dbSNP: rs80034299

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001043477	SCV001207226	pathogenic	Joubert syndrome 14	2022-08-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 841287). Disruption of this splice site has been observed in individual(s) with Joubert syndrome (PMID: 26673778). This variant is present in population databases (rs80034299, gnomAD 0.007%). This sequence change affects a donor splice site in intron 7 of the TMEM237 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 TMEM237 are known to be pathogenic (PMID: 22152675).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226424	SCV003922769	likely pathogenic	Joubert syndrome and related disorders	2023-03-07	criteria provided, single submitter	clinical testing	Variant summary: TMEM237 c.553+1G>A 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: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 248720 control chromosomes. c.553+1G>A has been reported as a compound heterozygous genotype with pathogenic variant and segregating with disease in an individual and aborted fetus affected with Joubert Syndrome And Related Disorders (Cui_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has 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 pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.