ClinVar Miner

Submissions for variant NM_001173990.3(TMEM216):c.218G>T (p.Arg73Leu) (rs201108965)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UW Hindbrain Malformation Research Program,University of Washington RCV000000220 SCV000256482 pathogenic Joubert syndrome 2 2015-02-23 criteria provided, single submitter research
GeneDx RCV000255378 SCV000322115 pathogenic not provided 2018-12-07 criteria provided, single submitter clinical testing The R73L pathogenic variant in the TMEM216 gene has been reported previously as a homozygous variant in individuals with Joubert syndrome and related disorders (JSRD) and appears to be a founder mutation among the Ashkenazi Jewish population (Edvardson et al., 2010; reported as R12L using alternate nomenclature). Additional studies have reported a significant decrease in TMEM216 protein production in cells transfected with R73L compared to the wild type and ciliogenesis disruption in TMEM216-R73L mutated fibroblasts in affected individuals (Lee et al., 2012; Valente et al., 2010). This variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R73L variant is a non-conservative amino acid substitution, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, other missense variants at the same amino acid position (R73C; R73H) have also been reported in association with Joubert syndrome and related disorders (Valente et al., 2010).
Counsyl RCV000409114 SCV000487403 pathogenic Meckel syndrome, type 2 2016-02-29 criteria provided, single submitter clinical testing
Invitae RCV000465185 SCV000554071 pathogenic Joubert syndrome 2020-10-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 73 of the TMEM216 protein (p.Arg73Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs201108965, ExAC 0.02%). This variant has been reported as homozygous and in combination with another TMEM216 variant in many individuals affected with Joubert syndrome and is a known founder mutation in the Ashkenazi Jewish population (PMID: 20036350, 20512146, 26092869, 26673778). ClinVar contains an entry for this variant (Variation ID: 197). Experimental studies have shown that this missense change leads to an unstable TMEM216 protein which disrupts normal ciliogenesis (PMID: 20512146, 22282472). Other missense substitutions at this codon (p.Arg73His and p.Arg73Cys) have been reported in individuals affected with Joubert syndrome (PMID: 20512146). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000000220 SCV000697775 pathogenic Joubert syndrome 2 2016-01-22 criteria provided, single submitter clinical testing Variant summary: The c.218G>T in TMEM216 gene is a missense variant that involves a non-conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant is present in the broad control population dataset of ExAC at a low frequency, exclusively in European cohort (0.024%), which does not exceed the maximum frequency for a pathogenic variant in TMEM216 gene (0.39%), suggesting this variant is not a common polymorphism. The variant has been reported in multiple affected individuals presented with JBTS2. This variant is considered to be a founder mutation in individuals of Ashkenazi Jewish descent. The carrier frequency in the Ashkenazi population was reported to be about 1:100 (Valente et al., 2010). The variant of interest has been reported as Pathogenic by several reputable databases. Taking together, the variant was classified as Pathogenic.
Ambry Genetics RCV000624413 SCV000741987 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255378 SCV000854899 pathogenic not provided 2017-10-26 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763259 SCV000893896 likely pathogenic Joubert syndrome 2; Meckel syndrome, type 2 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000779066 SCV000915533 pathogenic TMEM216-Related Disorders 2018-12-14 criteria provided, single submitter clinical testing The TMEM216 c.218G>T (p.Arg73Leu) missense variant is noted to be a founder variant in the Ashkenazi Jewish population (Parisi et al. 2013). Across a selection of available literature, the p.Arg73Leu variant has been identified in a total of 40 individuals with Joubert syndrome including 39 homozygotes and one compound heterozygote. The variant was also identified in a heterozygous state in 119 unaffected family members (Edvardson et al. 2010; Valente et al. 2010; Bachmann-Gagescu et al. 2015). Additionally the p.Arg73Leu variant was found in a homozygous state in a Turkish family in which Meckel syndrome and Joubert syndrome coexisted within the same sibship (Valente et al. 2010). The p.Arg73Leu variant was reported in 30 of 2766 anonymous Ashkenazi Jewish individuals in a heterozygous state and is reported at a frequency of 0.003381 in the Ashkenazi Jewish population of the Genome Aggregation Database. Lee et al. (2012) reported that fibroblasts from a patient carrying the p.Arg73Leu variant showed failure of ciliogenesis. Based on the collective evidence, the p.Arg73Leu variant is classified as pathogenic for TMEM216-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Myriad Women's Health, Inc. RCV000000220 SCV001193842 pathogenic Joubert syndrome 2 2019-11-12 criteria provided, single submitter clinical testing NM_001173990.2(TMEM216):c.218G>T(R73L) is classified as pathogenic in the context of Joubert syndrome 2. Sources cited for classification include the following: PMIDs: 20036350, 20512146, and 22282472. Classification of NM_001173990.2(TMEM216):c.218G>T(R73L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000000220 SCV001365595 pathogenic Joubert syndrome 2 2019-08-19 criteria provided, single submitter clinical testing The p.Arg73Leu variant (also called p.Arg12Leu) in TMEM216 is a founder variant in the Ashkenazi Jewish population and has been reported in the homozygous state in at least 20 individuals with Joubert syndrome or Meckel syndrome and segregated with disease in >10 affected individuals from at least 5 families (Edvardson 2010, Schueler 2016, Valente 2010). It has also been identified in 0.338% (35/10352) of Ashkenazi Jewish chromosomes by gnomAD ( However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has been reported in ClinVar (Variation ID: 197). Computational prediction tools and conservation analyses do not provide evidence for or against pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function (Valente 2010); however, these types of assays may not accurately represent biological function. Additionally, two variants at the same position (p.Arg73His and p.Arg73Leu) have been identified in individuals with Joubert syndrome, suggesting that a change at this position may not be tolerated. In summary, the p.Arg73Leu variant meets criteria to be classified as pathogenic for autosomal recessive Joubert syndrome. ACMG/AMP criteria applied: PM3_Strong, PP1_Strong, PS3_Supporting.
OMIM RCV000000220 SCV000020363 pathogenic Joubert syndrome 2 2010-07-01 no assertion criteria provided literature only
GeneReviews RCV000000220 SCV000058601 pathologic Joubert syndrome 2 2012-03-29 no assertion criteria provided curation Converted during submission to Pathogenic.
Natera, Inc. RCV000000220 SCV001460232 pathogenic Joubert syndrome 2 2020-09-16 no assertion criteria provided clinical testing

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