Submissions for variant NM_153704.6(TMEM67):c.628T>C (p.Ser210Pro)

gnomAD frequency: 0.00001  dbSNP: rs771718467

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004930	SCV001164448	uncertain significance	Joubert syndrome 6	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Ser210Pro variant in TMEM67 was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in one individual with Joubert syndrome. The presence of this variant in combination with a likely pathogenic variant and in an individual with Joubert syndrome increases the likelihood that the p.Ser210Pro variant is pathogenic. This variant has been identified in 0.003158% (4/126676) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs771718467). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ser210Pro variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3_Supporting, BP4 (Richards 2015).