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

dbSNP: rs201108965

Total submissions: 18

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	2022-05-03	criteria provided, single submitter	clinical testing	Published functional 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22282472, 27065010, 27175728, 28125082, 31624327, 31663226, 20512146, 21029074, 20036350, 20301500, 26092869)
Counsyl	RCV000409114	SCV000487403	pathogenic	Meckel syndrome, type 2	2016-02-29	criteria provided, single submitter	clinical testing
Invitae	RCV000465185	SCV000554071	pathogenic	Familial aplasia of the vermis	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 73 of the TMEM216 protein (p.Arg73Leu). This variant is present in population databases (rs201108965, gnomAD 0.4%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 20036350, 26092869). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 20036350, 20512146). ClinVar contains an entry for this variant (Variation ID: 197). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TMEM216 function (PMID: 20512146, 22282472). This variant disrupts the p.Arg73 amino acid residue in TMEM216. Other variant(s) that disrupt this residue have been observed in individuals with TMEM216-related conditions (PMID: 20512146), which suggests that this may be a clinically significant amino acid residue. 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	2022-12-01	criteria provided, single submitter	clinical testing	The c.218G>T (p.R73L) alteration is located in exon 3 (coding exon 3) of the TMEM216 gene. This alteration results from a G to T substitution at nucleotide position 218, causing the arginine (R) at amino acid position 73 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.016% (44/280628) total alleles studied. The highest observed frequency was 0.338% (35/10352) of Ashkenazi Jewish alleles. The alteration has been previously reported in multiple individuals with Joubert syndrome from Ashkenazi Jewish families (Edvardson, 2010; Valente, 2010; Bachmann-Gagescu, 2015; Schueler, 2016). Additionally, other variants at this amino acid position have been reported to cause disease (Lee, 2012). This amino acid position is highly conserved in available vertebrate species. Functional analysis on patient fibroblasts demonstrated the p.R73L alteration disrupted ciliogenesis (Lee, 2012). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000255378	SCV000854899	pathogenic	not provided	2017-10-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001787358	SCV000893896	pathogenic	Joubert syndrome 2; Meckel syndrome, type 2	2022-05-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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 Genetics, 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, Mass General Brigham 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 (http://gnomad.broadinstitute.org). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000255378	SCV001746994	pathogenic	not provided	2021-04-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255378	SCV003828084	pathogenic	not provided	2023-04-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000000220	SCV004206191	pathogenic	Joubert syndrome 2	2023-10-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003934786	SCV004754905	pathogenic	TMEM216-related condition	2023-12-19	criteria provided, single submitter	clinical testing	The TMEM216 c.218G>T variant is predicted to result in the amino acid substitution p.Arg73Leu. This variant has been reported as pathogenic in multiple patients with Joubert syndrome or Meckel syndrome (described as c.35G>T R12L, Edvardson et al. 2010. PubMed ID: 20036350; Valente et al. 2010. PubMed ID: 20512146; Table S5, Bachmann-Gagescu et al. 2015. PubMed ID: 26092869). This variant has been reported as a founder variant in the Ashkenazi Jewish population, and is reported in 0.34% of alleles in individuals of this descent in gnomAD. This variant is interpreted as pathogenic.
OMIM	RCV000000220	SCV000020363	pathogenic	Joubert syndrome 2	2010-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000000220	SCV000058601	not provided	Joubert syndrome 2		no assertion provided	literature only
Natera, Inc.	RCV000000220	SCV001460232	pathogenic	Joubert syndrome 2	2020-09-16	no assertion criteria provided	clinical testing